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Clinical Trial Results:
Phase 1b/2a Study Combining LY2157299 with Standard Temozolomide-based Radiochemotherapy in Patients with Newly Diagnosed Malignant Glioma

Summary
EudraCT number	2010-022160-13
Trial protocol	DE
Global end of trial date	23 Nov 2016

Results information
Results version number	v1(current)
This version publication date	07 Dec 2017
First version publication date	07 Dec 2017
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

H9H-MC-JBAI

ISRCTN number

US NCT number

NCT01220271

WHO universal trial number (UTN)

Other trial identifiers

Trial Number: 11585

Sponsor organisation name

Eli Lilly and Company

Sponsor organisation address

Lilly Corporate Center, Indianapolis, IN, United States, 46285

Public contact

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,

Scientific contact

Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company, 1 877‐285‐4559,

Sponsor organisation name

Eli Lilly and Company

Sponsor organisation address

Lilly Corporate Center, Indianapolis, IN, United States, 46285

Public contact

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,

Scientific contact

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,

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

23 Nov 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 Nov 2016

Was the trial ended prematurely?

Main objective of the trial

Phase 1b: To determine the safe and tolerable dose of galunisertib in combination with radiochemotherapy with temozolomide in participants with glioma eligible to receive radiochemotherapy with temozolomide (e.g. newly diagnosed malignant glioma World Health Organization Grade III and IV). Phase 2a: To confirm the tolerability and evaluate the pharmacodynamic effect of Galunisertib in combination with standard radiochemotherapy in participants with newly diagnosed glioblastoma.

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.

Background therapy

Radiation therapy.

Evidence for comparator

Actual start date of recruitment

21 Apr 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

35 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 35

Country: Number of subjects enrolled

Germany: 18

Country: Number of subjects enrolled

Spain: 22

Worldwide total number of subjects

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

Completers included participants who died from any cause and participants who were alive but off study treatment at study conclusion.

Screening details

No Text Entered

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1: 160 mg Galunisertib +TMZ+RTX

Arm description

During Radiation therapy: • Radiation(RTX):Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. • Galunisertib: 80 mg taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. • Temozolomide(TMZ): 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: • Galunisertib: 80 mg taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for 6 cycles. • Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. • For participants benefiting from therapy, treatment may continue in 2 cycle segments as long as benefit continues.

Arm type

Experimental

Investigational medicinal product name

Galunisertib

Investigational medicinal product code

Other name

LY2157299

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During Radiation therapy: •Galunisertib: 80 mg taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. After Radiation Therapy: •Galunisertib: 80 mg taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for 6 cycles.

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

After Radiation Therapy: •Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Phase 1: 300 mg Galunisertib +TMZ+RTX

Arm description

During Radiation therapy: • Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. • Galunisertib: 150 mg taken twice orally daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. • Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: • Galunisertib: 150 mg taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for 6 cycles. • For participants benefiting from therapy, treatment may continue in 2 cycle segments as long as benefit continues. • Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Arm type

Experimental

Investigational medicinal product name

Galunisertib

Investigational medicinal product code

Other name

LY2157299

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During Radiation therapy: •Galunisertib: 150 mg taken twice orally daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. After Radiation Therapy: •Galunisertib: 150 mg taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for 6 cycles.

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

During Radiation therapy: •Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: •Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Phase 2: 300 mg Galunisertib +TMZ+RTX

Arm description

During Radiation therapy: • Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. • Galunisertib: Phase 1 established dose taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. • Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: • Galunisertib: Phase 1 established dose taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for 6 cycles. • For participants benefiting from therapy, treatment may continue in 2 cycle segments as long as benefit continues. • Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Arm type

Experimental

Investigational medicinal product name

Galunisertib

Investigational medicinal product code

Other name

LY2157299

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During Radiation therapy: •Galunisertib: Phase 1 established dose taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. After Radiation Therapy: •Galunisertib: Phase 1 established dose taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for 6 cycles.

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Phase 2: TMZ+RTX

Arm description

During Radiation therapy: • Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. • Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Arm type

Active comparator

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Temozolomide

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

After Radiation Therapy: Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Number of subjects in period 1	Phase 1: 160 mg Galunisertib +TMZ+RTX	Phase 1: 300 mg Galunisertib +TMZ+RTX	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX
Started	10	9	40	16
Received at Least one dose of study drug	10	9	40	16
Completed	5	9	38	16
Not completed	5	0	2	0
Consent withdrawn by subject	4	-	2	-
Lost to follow-up	1	-	-	-

Baseline characteristics

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Reporting group title

Phase 1: 160 mg Galunisertib +TMZ+RTX

Reporting group description

Reporting group title

Phase 1: 300 mg Galunisertib +TMZ+RTX

Reporting group description

Reporting group title

Phase 2: 300 mg Galunisertib +TMZ+RTX

Reporting group description

During Radiation therapy: • Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. • Galunisertib: Phase 1 established dose taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. • Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: • Galunisertib: Phase 1 established dose taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for 6 cycles. • For participants benefiting from therapy, treatment may continue in 2 cycle segments as long as benefit continues. • Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Reporting group title

Phase 2: TMZ+RTX

Reporting group description

During Radiation therapy: • Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. • Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Reporting group values	Phase 1: 160 mg Galunisertib +TMZ+RTX	Phase 1: 300 mg Galunisertib +TMZ+RTX	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX	Total
Number of subjects	10	9	40	16	75
Age categorical
All participants who received at least one dose of study drug.
Units: Subjects
In utero					0
Preterm newborn infants (gestational age < 37 wks)					0
Newborns (0-27 days)					0
Infants and toddlers (28 days-23 months)					0
Children (2-11 years)					0
Adolescents (12-17 years)					0
Adults (18-64 years)					0
From 65-84 years					0
85 years and over					0
Age Continuous
All participants who received at least one dose of study drug.
Units: years
arithmetic mean (standard deviation)	52.3 ± 8.1	57.6 ± 12.3	58.7 ± 8.9	57.8 ± 11.6	-
Gender categorical
All participants who received at least one dose of study drug.
Units: Subjects
Female	3	4	18	5	30
Male	7	5	22	11	45
Sex: Female, Male
All participants who received at least one dose of study drug.
Units: Subjects
Female	3	4	18	5	30
Male	7	5	22	11	45
Race (NIH/OMB)
All participants who received at least one dose of study drug.
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	0	0	1	1	2
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	0	0	0	0
White	10	9	39	15	73
More than one race	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0
Region of Enrollment
All participants who received at least one dose of study drug.
Units: Subjects
United States	2	2	25	6	35
Germany	4	4	6	4	18
Spain	4	3	9	6	22

End points

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Reporting group title

Phase 1: 160 mg Galunisertib +TMZ+RTX

Reporting group description

Reporting group title

Phase 1: 300 mg Galunisertib +TMZ+RTX

Reporting group description

Reporting group title

Phase 2: 300 mg Galunisertib +TMZ+RTX

Reporting group description

During Radiation therapy: • Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. • Galunisertib: Phase 1 established dose taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. • Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: • Galunisertib: Phase 1 established dose taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for 6 cycles. • For participants benefiting from therapy, treatment may continue in 2 cycle segments as long as benefit continues. • Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Reporting group title

Phase 2: TMZ+RTX

Reporting group description

During Radiation therapy: • Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. • Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Subject analysis set title

Phase 1b Participants

Subject analysis set type

Intention-to-treat

Subject analysis set description

During Radiation therapy: •Radiation(RTX):Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose= 60.0 Gy per week for 6 weeks. Radiation was administered as approved. •Galunisertib: 80 mg or 150 mg taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days •Temozolomide(TMZ): 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: •Galunisertib: 80 mg or 150 mg taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for 6 cycles •For participants benefiting from therapy, treatment may continue in 2 cycle segments as long as benefit continues. •Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Primary: Phase 1b: Recommended Dose for Phase 2a Portion : Maximum Tolerated Dose (MTD)

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End point title

Phase 1b: Recommended Dose for Phase 2a Portion : Maximum Tolerated Dose (MTD) ^[1]

End point description

MTD was determined by evaluation of overall safety, dose reductions, omissions,& PK information from Phase1b.Toxicities were graded according to the National Cancer Institute’s(NCI)Common Terminology Criteria for Adverse Events (CTCAE) v4.0. If multiple toxicities are seen, the presence of Dose-limiting toxicities (DLT)was based on the most severe toxicity experienced. DLTs were defined as any of the following events, which occur during radiochemotherapy & galunisertib attributable to galunisertib or the combination of galunisertib with radiation and/or TMZ and which last longer than 7 days: any Grade > 3 thrombocytopenia, and Grade 4 anemia and neutropenia any non-hematologic Grade > 3 toxicity(including nausea, vomiting, or diarrhea which can't be controlled with optimal medical management within 48 hours)any Grade 4 radiation-induced skin changes failure to recover from toxicities to be eligible for retreatment with galunisertib.

End point type

Primary

End point timeframe

Baseline to phase 1 Completion (Up to 10 Weeks) Analysis Population Description (APD): Phase 1b: All participants who received at least one dose of study drug.

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 arm comparison analyses were planned or conducted.

End point values	Phase 1b Participants
Number of subjects analysed	19
Units: mg
number (not applicable)	300

No statistical analyses for this end point

Secondary: Phase 2a: Relationship of Change in Response Biomarkers to Clinical Benefit (Overall Survival (OS) of Change in Biomarkers)

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End point title

Phase 2a: Relationship of Change in Response Biomarkers to Clinical Benefit (Overall Survival (OS) of Change in Biomarkers) ^[2]

End point description

Change from baseline in the biomarker at the end of cycle 5 for each participant was calculated and each participant was then classified as being ‘less than’ or ‘greater than or equal to’ the median change from baseline. Median overall survival (months) and 90% confidence intervals (where participant's numbers allowed) were estimated for each treatment/biomarker category combination. APD: All phase 2a participants randomized onto one of the study treatment arms and who completed 5 cycles of treatment. 4 participants in the control arm were combined into 300 mg Galunisertib + TMZ+RTX arm since there was insufficient data to estimate parameters in control arm. TRegs= CD4+CD25+CD127-/LOFOX P3+ 9999= Not estimable. Too few data to estimate. Data were estimated from a Kaplan-Meier Model and not raw data.

End point type

Secondary

End point timeframe

Baseline Through Discontinuation From Study For Any Cause (Up To 35 Months)

Notes
[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: Analyses were only planned for Phase 2a.

End point values	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX
Number of subjects analysed	31 ^[3]	4 ^[4]
Units: Months
median (confidence interval 90%)
OS;CD3+ change in biomarker<median change(n=15,2)	20.0 (13.4 to 25.2)	9999 (9999 to 9999)
OS;CD3+ change in biomarker>=median change(n=16,2)	18.7 (15.3 to 28.5)	9999 (9999 to 9999)
OS;CD4+ change in biomarker<median change(n=15,2)	19.2 (12.8 to 24.4)	9999 (9999 to 9999)
OS;CD4+ change in biomarker>=median change(n=16,2)	19.6 (17.2 to 28.5)	9999 (9999 to 9999)
OS;CD8+ change in biomarker<median change(n=15,2)	22.3 (19.2 to 9999)	9999 (9999 to 9999)
OS;CD8+ change in biomarker>=median change(n=16,2)	16.3 (11.6 to 22.0)	9999 (9999 to 9999)
OS;TRegs change in biomarker<median change(n=15,2)	15.3 (11.7 to 20.0)	9999 (9999 to 9999)
OS;TRegs change biomarker>=median change(n=16,2)	25.2 (18.2 to 9999)	9999 (9999 to 9999)
OS;YKL-40 change biomarker<median change(n=16,2)	18.7 (11.7 to 26.3)	9999 (9999 to 9999)
OS;YKL-40 change biomarker>=median change(n=16,2)	19.9 (15.3 to 28.5)	9999 (9999 to 9999)

Notes
[3] - 9999= Not estimable. Too few data to estimate.
[4] - 9999= Not estimable. Too few data to estimate.

No statistical analyses for this end point

Secondary: Phase 1b: Pharmacokinetics (PK) - Maximum Observed Drug Concentration at Steady (Cmax ss)

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End point title

Phase 1b: Pharmacokinetics (PK) - Maximum Observed Drug Concentration at Steady (Cmax ss) ^[5]

End point description

Maximum Observed Drug Concentration (Cmax ss). APD: Phase 1b: All participants who received at least one dose of study drug and had evaluable PK data. Geometric coefficient of variation is a % and not ±. Due to system limitation we could not add a %.

End point type

Secondary

End point timeframe

Cycle 1: Day 14, Predose, 0.5,2,3,6 h; Day 15 (morning, 24h postdose), Day 16 (morning, 48h postdose); Cycle 2 and Cycle 3: Day 14: Predose, 0.5,2,3,6 h; Day 15 (morning,24h postdose)

Notes
[5] - 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: Analyses were only planned for Phase 1b.

End point values	Phase 1: 160 mg Galunisertib +TMZ+RTX	Phase 1: 300 mg Galunisertib +TMZ+RTX
Number of subjects analysed	10	9
Units: Nanograms/milliliter (ng/mL)
geometric mean (geometric coefficient of variation)
Cycle 1(n=10,8)	653 ± 91	1620 ± 70
Cycle 2(n=8,8)	580 ± 75	1160 ± 48
Cycle 3(n=5,7)	728 ± 67	1550 ± 47

No statistical analyses for this end point

Secondary: Phase 1b: PK - Time of Maximum Observed Drug Concentration at Steady State (Tmax ss)

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End point title

Phase 1b: PK - Time of Maximum Observed Drug Concentration at Steady State (Tmax ss) ^[6]

End point description

Time of Maximum Observed Drug Concentration (Tmax ss) APD: Phase 1b: All participants who received at least one dose of study drug and had evaluable PK data.

End point type

Secondary

End point timeframe

Cycle 1: Day 14, Predose, 0.5,2,3,6 h; Day 15 (morning, 24h postdose), Day 16 (morning, 48h postdose); Cycle 2 and Cycle 3: Day 14: Predose, 0.5,2,3,6 h; Day 15 (morning,24h postdose)

Notes
[6] - 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: Analyses were only planned for Phase 1b.

End point values	Phase 1: 160 mg Galunisertib +TMZ+RTX	Phase 1: 300 mg Galunisertib +TMZ+RTX
Number of subjects analysed	10	9
Units: Hours (h)
median (full range (min-max))
Cycle 1 (n=10,8)	1.29 (0.5 to 3)	1.21 (0.5 to 3)
Cycle 2 (n=8,8)	1.13 (0.5 to 3)	1.5 (0.5 to 2)
Cycle 3 (n=5,7)	0.75 (0.48 to 2)	1 (0.5 to 2.08)

No statistical analyses for this end point

Secondary: Phase 1b: PK - Area Under the Concentration-Time Curve at Steady State From Time Zero to Infinity (AUC[0-∞],ss)

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End point title

Phase 1b: PK - Area Under the Concentration-Time Curve at Steady State From Time Zero to Infinity (AUC[0-∞],ss) ^[7]

End point description

Area Under the Concentration-Time Curve From Time Zero to Infinity. APD: Phase 1b: All participants who received at least one dose of study drug and had evaluable PK data. Geometric coefficient of variation is a % and not ±. Due to system limitation we could not add a %.

End point type

Secondary

End point timeframe

Cycle 1: Day 14, Predose, 0.5,2,3,6 h; Day 15 (morning, 24h postdose), Day 16 (morning, 48h postdose); Cycle 2 and Cycle 3: Day 14: Predose, 0.5,2,3,6 h; Day 15 (morning,24h postdose)

Notes
[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: Analyses were only planned for Phase 1b.

End point values	Phase 1: 160 mg Galunisertib +TMZ+RTX	Phase 1: 300 mg Galunisertib +TMZ+RTX
Number of subjects analysed	10	9
Units: Hournanogram per milliliter (hng/mL)
geometric mean (geometric coefficient of variation)
Cycle 1 (n=10,8)	1860 ± 93	6290 ± 70
Cycle 2(n=8,8)	1910 ± 89	4940 ± 35
Cycle 3(n=5,7)	1920 ± 104	5510 ± 27

No statistical analyses for this end point

Secondary: Phase 1b: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR])

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End point title

Phase 1b: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR]) ^[8]

End point description

ORR rate is the best response of complete response(CR) or partial response(PR) as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors(RECIST v1.1).CR is the complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks and participants must be off corticosteroids and stable or improved clinically.PR is greater than or equal to 50% decrease,compared to baseline,in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. Progression(PD) was defined as having at least a 25% increase in the sum of the longest diameter of target lesions. Stable disease(SD) occurred when a participant did not qualify for CR,PR, or PD. ORR calculated as sum of the number of participants with PRs and CRs divided by the number of patients treated, expressed as a percentage. APD: Phase 1b: All participants who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline to Progressive Disease (Up to 46 Months)

Notes
[8] - 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: Analyses were only planned for Phase 1b.

End point values	Phase 1: 160 mg Galunisertib +TMZ+RTX	Phase 1: 300 mg Galunisertib +TMZ+RTX
Number of subjects analysed	10	9
Units: Percentage of participants
number (not applicable)	10.00	11.11

No statistical analyses for this end point

Secondary: Phase 2a: Percentage Overall Survival at 12 Months

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End point title

Phase 2a: Percentage Overall Survival at 12 Months ^[9]

End point description

Overall survival duration is measured from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date for a particular analysis, overall survival duration was censored for that analysis at the date of last prior contact. APD: Phase 2a: All participants who received at least one dose of study drug. Number of participants censored were Galunisertib + TMZ+RTX= 9 and TMZ+RTX= 5.

End point type

Secondary

End point timeframe

Randomization to Date of Death from any Cause at 12 Months

Notes
[9] - 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: Analyses were only planned for Phase 2a.

End point values	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX
Number of subjects analysed	40	16
Units: Percentage alive at 12 months
arithmetic mean (confidence interval 90%)	74 (59 to 83)	80 (56 to 92)

No statistical analyses for this end point

Secondary: Phase 2a: Overall Survival

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End point title

Phase 2a: Overall Survival ^[10]

End point description

Overall survival duration is measured from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date for a particular analysis, overall survival duration will be censored for that analysis at the date of last prior contact. APD: Phase 2a: All participants who received at least one dose of study drug. Number of participants censored were Galunisertib + TMZ+RTX= 9 and TMZ+RTX= 5.

End point type

Secondary

End point timeframe

Randomization to Date of Death from Any Cause (Up to 35 Months)

Notes
[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: Analyses were only planned for Phase 2a.

End point values	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX
Number of subjects analysed	40	16
Units: Months
median (confidence interval 95%)	18.2 (13.4 to 20.6)	17.9 (10.7 to 24.0)

statistical_analysis_Overall Survival

Statistical analysis description

Regression Cox methodology was used to calculate the hazard ratio.

Comparison groups

Phase 2: TMZ+RTX v Phase 2: 300 mg Galunisertib +TMZ+RTX

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.2

Confidence interval

level

90%

sides

2-sided

lower limit

0.7

upper limit

2.1

Secondary: Phase 2a: Progression Free Survival (PFS)

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End point title

Phase 2a: Progression Free Survival (PFS) ^[11]

End point description

PFS is defined as the date of randomization to the first date of progression of disease or of death from any cause. For each participant who is not known to have died or to have had a progression of disease as of the data-inclusion cut-off date for a particular analysis, PFS will be censored at the date of last prior contact. PFS will be calculated and analyzed twice: (1) including clinical progressions of disease not based on lesion measurements, and (2) excluding clinical progressions. Progression(PD) was defined as having at least a 25% increase in the sum of the longest diameter of target lesions. APD: Phase 2a: All participants who received at least one dose of study drug. Number of participants censored were Galunisertib + TMZ+RTX = 3 and TMZ+RTX= 3.

End point type

Secondary

End point timeframe

Randomization to Measured Progressive Disease or Death From Any Cause(Up to 35 Months)

Notes
[11] - 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: Analyses were only planned for Phase 2a.

End point values	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX
Number of subjects analysed	40	16
Units: Months
median (confidence interval 95%)	7.6 (6.1 to 10.4)	11.5 (5.4 to 15.9)

No statistical analyses for this end point

Secondary: Phase 2a: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR])

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End point title

Phase 2a: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) ^[12]

End point description

ORR rate is the best response of complete response(CR) or partial response(PR) as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors(RECIST v1.1).CR is the complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks and participants must be off corticosteroids and stable or improved clinically.PR is greater than or equal to 50% decrease,compared to baseline,in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. Progression(PD) was defined as having at least a 25% increase in the sum of the longest diameter of target lesions. Stable disease(SD) occurred when a participant did not qualify for CR,PR, or PD.ORR calculated as sum of the number of participants with PRs and CRs divided by the number of patients treated, expressed as a percentage. APD: Phase 2a : All participants who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Randomization to Measured Progressive Disease(Up to 35 Months)

Notes
[12] - 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: Analyses were only planned for Phase 2a.

End point values	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX
Number of subjects analysed	40	16
Units: Percentage of participants
number (not applicable)	7.50	0.00

No statistical analyses for this end point

Secondary: Phase 2a: Duration of tumor Response

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End point title

Phase 2a: Duration of tumor Response ^[13]

End point description

APD: Zero participants were analyzed.The data were not evaluable.Only three participants were responders and so duration of tumor was not evaluable.

End point type

Secondary

End point timeframe

Time of Response to Measured Progressive Disease or Death Due to any Cause(Up To 35 Months)

Notes
[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: Analyses were only planned for Phase 2a.

End point values	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX
Number of subjects analysed	0 ^[14]	0 ^[15]
Units: months
median (confidence interval 95%)	( to )	( to )

Notes
[14] - Zero participants were analyzed.The data were not evaluable.
[15] - Zero participants were analyzed.The data were not evaluable.

No statistical analyses for this end point

Secondary: Phase 2a: Time to Treatment Failure

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End point title

Phase 2a: Time to Treatment Failure ^[16]

End point description

Time to treatment failure is measured from the date of randomization until the date of discontinuation of study treatment due to adverse event, progression of disease, or death from any cause. For each participant who discontinued study treatment for any other reason, time to treatment failure will be censored at the date of discontinuation of study treatment. If a participant is still on study treatment as of the data-inclusion cut-off date for the particular analysis, time to treatment failure will be censored for that participant at that cut-off date. Progression(PD) was defined as having at least a 25% increase in the sum of the longest diameter of target lesions. APD: Phase 2a: All participants who received at least one dose of study drug. Number of participants censored were Galunisertib + TMZ+RTX=9 and TMZ+RTX= 9.

End point type

Secondary

End point timeframe

Randomization to the Date of Discontinuation of Study Treatment Due to Adverse Event, Progression of Disease, or Death from Any Cause(Up to 35 Months)

Notes
[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: Analyses were only planned for Phase 2a.

End point values	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX
Number of subjects analysed	40	16 ^[17]
Units: Months
median (confidence interval 95%)	7.1 (5.5 to 8.9)	8.8 (5.1 to 9999)

Notes
[17] - 9999= Not estimable. Too many censored values.

No statistical analyses for this end point

Secondary: Phase 2a: Change from baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) - Brain Tumor Symptoms, Core Symptoms, Interference Symptoms

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End point title

Phase 2a: Change from baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) - Brain Tumor Symptoms, Core Symptoms, Interference Symptoms ^[18]

End point description

The MDASI-BT consists of 22 symptom items (13 items of the core MDASI plus 9 items specific to brain tumors) plus 6 interference items, all with 11-point rating scales. For the symptom items, 0 equals “not present” and 10 equals “as bad as you can imagine.” For the interference items, 0 equals “did not interfere” and 10 equals “interfered completely. The brain tumor symptoms, core symptoms and interference symptoms range 0 to 10 with lower scores indicating that the participant is reporting fewer symptoms or less interference. APD: Phase 2a: All participants who received at least one dose of study drug and had a baseline and at least one post-baseline measurement.

End point type

Secondary

End point timeframe

Baseline, 30 Day Post Study Day Follow-Up

Notes
[18] - 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: Analyses were only planned for Phase 2a.

End point values	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX
Number of subjects analysed	22	12
Units: units on a scale
arithmetic mean (standard deviation)
Brain Tumor Symptoms	0.2 ± 1.3	0.2 ± 1.7
Core Symptoms	0.7 ± 1.1	0.6 ± 1.4
Interference Symptoms	0.8 ± 2.1	0.2 ± 2.2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Phase 1b/2a - Entire Study

Adverse event reporting additional description

All participants who received at least one dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Phase 1: 160 mg Galunisertib +TMZ+RTX

Reporting group description

During Radiation therapy: •Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. •Galunisertib: 80 mg taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. •Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: •Galunisertib: 80 mg taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for a 6 cycles. •Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. •For participants benefiting from therapy, treatment may continue in 2 cycle segments as long as benefit continues.

Reporting group title

Phase 1: 300 mg Galunisertib +TMZ+RTX

Reporting group description

During Radiation therapy: •Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. •Galunisertib: 150 mg taken twice orally daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. •Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: •Galunisertib: 150 mg taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for a 6 cycles. •For participants benefiting from therapy, treatment may continue in 2 cycle segments as long as benefit continues. •Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Reporting group title

Phase 2: 300 mg Galunisertib +TMZ+RTX

Reporting group description

During Radiation therapy: •Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. •Galunisertib: Phase 1 established dose taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. •Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: •Galunisertib: Phase 1 established dose taken orally twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for a 6 cycles. •For participants benefiting from therapy, treatment may continue in 2 cycle segments as long as benefit continues. •Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Reporting group title

Phase 2: TMZ+RTX

Reporting group description

During Radiation therapy: •Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions taken 5 days per week. Approximate total dose = 60.0 Gy per week for 6 weeks. Radiation was administered as approved. •Temozolomide: 75 mg/m2 taken orally daily for 6 weeks. After Radiation Therapy: Temozolomide: 150 mg/m2 and then 200 mg/m2 orally daily during the off time of galunisertib. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.

Serious adverse events	Phase 1: 160 mg Galunisertib +TMZ+RTX	Phase 1: 300 mg Galunisertib +TMZ+RTX	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 10 (40.00%)	2 / 9 (22.22%)	20 / 40 (50.00%)	5 / 16 (31.25%)
number of deaths (all causes)	0	0	0	1
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
metastases to spine
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
tumour haemorrhage
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
deep vein thrombosis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
pyrexia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
pneumonia aspiration
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
pneumonitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
pulmonary embolism
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
confusional state
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
mental status changes
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
alanine aminotransferase increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
neutrophil count decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
platelet count decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
white blood cell count decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
postoperative fever
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
atrial fibrillation
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
cardiac failure
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
ataxia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
brain oedema
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
central nervous system necrosis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
cerebral haemorrhage
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
epilepsy
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
haemorrhage intracranial
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
neurological symptom
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
seizure
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	2 / 16 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
syncope
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
anaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
febrile neutropenia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
neutropenia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
thrombocytopenia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 10 (20.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
diarrhoea
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
enteritis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
large intestine perforation
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
nausea
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
retroperitoneal haemorrhage
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
acute kidney injury
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
pain in extremity
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
gastroenteritis viral
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
pneumonia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
septic shock
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
wound infection
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
hypokalaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase 1: 160 mg Galunisertib +TMZ+RTX	Phase 1: 300 mg Galunisertib +TMZ+RTX	Phase 2: 300 mg Galunisertib +TMZ+RTX	Phase 2: TMZ+RTX
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 10 (100.00%)	9 / 9 (100.00%)	39 / 40 (97.50%)	16 / 16 (100.00%)
Vascular disorders
arterial haemorrhage
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
deep vein thrombosis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	3 / 16 (18.75%)
occurrences all number	0	1	4	3
haematoma
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
hypertension
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	1	0	0
hypotension
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences all number	0	1	1	0
lymphoedema
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
orthostatic hypotension
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
thrombophlebitis superficial
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
General disorders and administration site conditions
asthenia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	3 / 10 (30.00%)	1 / 9 (11.11%)	6 / 40 (15.00%)	3 / 16 (18.75%)
occurrences all number	3	1	6	3
face oedema
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 16 (0.00%)
occurrences all number	0	0	3	0
fatigue
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	5 / 10 (50.00%)	6 / 9 (66.67%)	24 / 40 (60.00%)	7 / 16 (43.75%)
occurrences all number	6	8	27	10
gait disturbance
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	5 / 40 (12.50%)	0 / 16 (0.00%)
occurrences all number	1	0	6	0
influenza like illness
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences all number	0	1	4	0
localised oedema
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences all number	0	1	1	0
malaise
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
oedema peripheral
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	1 / 16 (6.25%)
occurrences all number	1	0	4	1
pyrexia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	3 / 40 (7.50%)	1 / 16 (6.25%)
occurrences all number	1	1	4	2
Immune system disorders
hypersensitivity
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences all number	1	0	2	0
Respiratory, thoracic and mediastinal disorders
benign prostatic hyperplasia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed ^[1]	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	1
cough
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	5 / 40 (12.50%)	1 / 16 (6.25%)
occurrences all number	2	0	5	1
dyspnoea
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences all number	1	0	2	0
nasal congestion
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 16 (6.25%)
occurrences all number	0	0	1	2
paranasal sinus discomfort
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
productive cough
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences all number	1	0	1	0
Psychiatric disorders
aggression
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
anxiety
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	1 / 16 (6.25%)
occurrences all number	1	0	3	1
bulimia nervosa
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
confusional state
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	5 / 40 (12.50%)	1 / 16 (6.25%)
occurrences all number	0	1	9	1
depression
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	4 / 40 (10.00%)	3 / 16 (18.75%)
occurrences all number	0	1	4	3
insomnia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	8 / 40 (20.00%)	6 / 16 (37.50%)
occurrences all number	1	1	8	6
irritability
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
Investigations
alanine aminotransferase increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 10 (20.00%)	1 / 9 (11.11%)	7 / 40 (17.50%)	2 / 16 (12.50%)
occurrences all number	2	1	11	4
aspartate aminotransferase increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	4 / 40 (10.00%)	1 / 16 (6.25%)
occurrences all number	1	1	7	4
blood bilirubin increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 16 (0.00%)
occurrences all number	0	0	3	0
blood creatinine increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences all number	1	0	2	0
gamma-glutamyltransferase increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
lipase increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	4 / 40 (10.00%)	1 / 16 (6.25%)
occurrences all number	1	1	6	2
lymphocyte count decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 10 (20.00%)	2 / 9 (22.22%)	7 / 40 (17.50%)	2 / 16 (12.50%)
occurrences all number	3	2	15	2
neutrophil count decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	4 / 40 (10.00%)	2 / 16 (12.50%)
occurrences all number	0	0	10	2
platelet count decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	11 / 40 (27.50%)	4 / 16 (25.00%)
occurrences all number	0	1	17	9
weight decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	2 / 9 (22.22%)	7 / 40 (17.50%)	2 / 16 (12.50%)
occurrences all number	1	2	8	2
weight increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	5 / 40 (12.50%)	1 / 16 (6.25%)
occurrences all number	0	0	5	1
white blood cell count decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	12 / 40 (30.00%)	1 / 16 (6.25%)
occurrences all number	1	0	30	5
Injury, poisoning and procedural complications
contusion
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
fall
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	7 / 40 (17.50%)	0 / 16 (0.00%)
occurrences all number	0	0	9	0
radiation skin injury
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	5 / 10 (50.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences all number	5	0	2	0
wound
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
Cardiac disorders
palpitations
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
sinus tachycardia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
Nervous system disorders
amnesia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences all number	0	1	1	0
aphasia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	2 / 9 (22.22%)	10 / 40 (25.00%)	0 / 16 (0.00%)
occurrences all number	1	2	10	0
ataxia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 16 (0.00%)
occurrences all number	0	0	3	0
balance disorder
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
cognitive disorder
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences all number	0	1	2	0
dizziness
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	6 / 40 (15.00%)	6 / 16 (37.50%)
occurrences all number	1	1	12	10
dysarthria
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	4 / 40 (10.00%)	2 / 16 (12.50%)
occurrences all number	0	1	4	2
dysgeusia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 16 (0.00%)
occurrences all number	1	0	3	0
facial paralysis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	4 / 40 (10.00%)	0 / 16 (0.00%)
occurrences all number	0	0	4	0
headache
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	5 / 10 (50.00%)	4 / 9 (44.44%)	15 / 40 (37.50%)	5 / 16 (31.25%)
occurrences all number	10	4	23	8
hemiparesis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	6 / 40 (15.00%)	0 / 16 (0.00%)
occurrences all number	0	0	7	0
hypoaesthesia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 16 (0.00%)
occurrences all number	0	0	3	0
memory impairment
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	8 / 40 (20.00%)	2 / 16 (12.50%)
occurrences all number	0	0	8	2
monoparesis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	2 / 9 (22.22%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	2	0	0
myoclonus
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
paraesthesia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 16 (0.00%)
occurrences all number	0	0	3	0
paresis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
peripheral sensory neuropathy
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 16 (0.00%)
occurrences all number	0	0	4	0
quadriplegia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
seizure
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	7 / 40 (17.50%)	1 / 16 (6.25%)
occurrences all number	0	1	10	1
sinus headache
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
somnolence
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
syncope
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 16 (6.25%)
occurrences all number	0	0	1	1
tremor
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	5 / 40 (12.50%)	1 / 16 (6.25%)
occurrences all number	1	0	5	1
Blood and lymphatic system disorders
anaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 10 (20.00%)	0 / 9 (0.00%)	6 / 40 (15.00%)	0 / 16 (0.00%)
occurrences all number	2	0	8	0
haemorrhagic diathesis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
leukopenia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	2 / 9 (22.22%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	3	0	0
lymphadenopathy
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
lymphopenia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 10 (20.00%)	4 / 9 (44.44%)	6 / 40 (15.00%)	1 / 16 (6.25%)
occurrences all number	2	4	14	2
neutropenia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	3 / 9 (33.33%)	2 / 40 (5.00%)	1 / 16 (6.25%)
occurrences all number	0	3	3	3
thrombocytopenia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	6 / 10 (60.00%)	3 / 9 (33.33%)	7 / 40 (17.50%)	0 / 16 (0.00%)
occurrences all number	9	3	8	0
Ear and labyrinth disorders
hypoacusis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 16 (6.25%)
occurrences all number	0	0	2	1
vertigo
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
Eye disorders
blindness
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
lacrimation increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
vision blurred
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	1 / 16 (6.25%)
occurrences all number	0	0	4	1
vitreous haemorrhage
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
Gastrointestinal disorders
abdominal distension
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 16 (0.00%)
occurrences all number	0	0	3	0
abdominal pain
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 10 (20.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 16 (0.00%)
occurrences all number	2	0	3	0
abdominal pain upper
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences all number	0	1	1	0
anal incontinence
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
constipation
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	4 / 10 (40.00%)	1 / 9 (11.11%)	20 / 40 (50.00%)	7 / 16 (43.75%)
occurrences all number	8	2	26	8
diarrhoea
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	1 / 16 (6.25%)
occurrences all number	0	0	5	1
dry mouth
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 16 (6.25%)
occurrences all number	0	0	2	1
dyspepsia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 10 (20.00%)	2 / 9 (22.22%)	6 / 40 (15.00%)	1 / 16 (6.25%)
occurrences all number	2	2	6	2
dysphagia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences all number	1	0	1	0
eructation
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 16 (6.25%)
occurrences all number	0	0	1	1
flatulence
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	0	0	2
gastrooesophageal reflux disease
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences all number	1	0	2	0
nausea
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	8 / 10 (80.00%)	2 / 9 (22.22%)	21 / 40 (52.50%)	10 / 16 (62.50%)
occurrences all number	13	2	34	13
paraesthesia oral
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
stomatitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
toothache
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
vomiting
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	3 / 10 (30.00%)	5 / 9 (55.56%)	13 / 40 (32.50%)	6 / 16 (37.50%)
occurrences all number	4	7	24	6
Skin and subcutaneous tissue disorders
alopecia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	4 / 10 (40.00%)	1 / 9 (11.11%)	15 / 40 (37.50%)	3 / 16 (18.75%)
occurrences all number	4	1	15	3
decubitus ulcer
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
dermatitis acneiform
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 10 (20.00%)	2 / 9 (22.22%)	3 / 40 (7.50%)	0 / 16 (0.00%)
occurrences all number	2	2	3	0
dermatitis allergic
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences all number	0	1	2	0
dermatitis bullous
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
dry skin
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	4 / 40 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	1	5	0
ecchymosis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences all number	1	1	2	0
erythema
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	1 / 16 (6.25%)
occurrences all number	1	0	3	1
erythema multiforme
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
pruritus
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	5 / 40 (12.50%)	0 / 16 (0.00%)
occurrences all number	1	0	6	0
rash
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	5 / 40 (12.50%)	1 / 16 (6.25%)
occurrences all number	0	0	9	1
rash maculo-papular
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	3 / 10 (30.00%)	1 / 9 (11.11%)	5 / 40 (12.50%)	0 / 16 (0.00%)
occurrences all number	3	1	7	0
skin exfoliation
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
skin lesion
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
Renal and urinary disorders
dysuria
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
nocturia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1
polyuria
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
urinary incontinence
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	4 / 40 (10.00%)	0 / 16 (0.00%)
occurrences all number	0	0	4	0
urinary retention
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 16 (0.00%)
occurrences all number	0	0	3	0
Endocrine disorders
hypothyroidism
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	1	0	0
Musculoskeletal and connective tissue disorders
arthralgia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	6 / 40 (15.00%)	1 / 16 (6.25%)
occurrences all number	0	1	7	1
back pain
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	7 / 40 (17.50%)	1 / 16 (6.25%)
occurrences all number	0	0	8	1
joint range of motion decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
muscular weakness
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	2 / 16 (12.50%)
occurrences all number	0	1	1	3
musculoskeletal pain
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences all number	2	1	1	0
myalgia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	1 / 16 (6.25%)
occurrences all number	0	0	5	1
pain in extremity
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	1 / 16 (6.25%)
occurrences all number	0	1	4	1
tendonitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
Infections and infestations
candida infection
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	4 / 40 (10.00%)	0 / 16 (0.00%)
occurrences all number	0	0	5	0
herpes simplex
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
oral herpes
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
rhinitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences all number	0	1	1	0
tooth infection
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0
upper respiratory tract infection
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 16 (0.00%)
occurrences all number	1	0	2	0
urinary tract infection
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences all number	1	0	1	0
Metabolism and nutrition disorders
decreased appetite
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	5 / 10 (50.00%)	1 / 9 (11.11%)	11 / 40 (27.50%)	3 / 16 (18.75%)
occurrences all number	5	1	18	3
hypercalcaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0
hyperglycaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 10 (20.00%)	1 / 9 (11.11%)	6 / 40 (15.00%)	2 / 16 (12.50%)
occurrences all number	3	1	7	2
hypermagnesaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	2
hypernatraemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	1 / 16 (6.25%)
occurrences all number	0	1	3	4
hypertriglyceridaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	1	0	0
hypokalaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	1 / 9 (11.11%)	4 / 40 (10.00%)	2 / 16 (12.50%)
occurrences all number	1	1	7	5
hyponatraemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 16 (0.00%)
occurrences all number	1	0	1	0
hypophosphataemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	0	0	0
polydipsia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.

More information

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Were there any global substantial amendments to the protocol? Yes

25 Feb 2013

Amendment b - With the growing understanding of the safety profile of LY2157299 across all studies and to ensure that appropriate data are being collected, the following changes to the protocol have been made: 1. Pharmacodynamics (PD) markers which were identified in other studies to provide no scientific information on the activity of LY2157299, were removed. 2. While ECHO cardiography/Doppler will remain unchanged for this study, ECG (except for screening at baseline) and ECG chemistry will be removed because no medically significant changes were observed with the administration of LY2157299 (ie,PK-associated QTc prolongations). 3. Clarification, updates and information on the Phase 1b safety review was included.

08 Jul 2014

Amendment c The protocol was amended to reduce the number of visits and tests required for patients on Cycles 15 and beyond. Based on the current safety profile of LY2157299, the reduction in the number of visits and tests would have no influence on the risk assessment. Additionally, continued access to LY2157299 was offered to participants who continued to experience clinical benefit, had no undue risks, and were on study treatment at the time of study completion.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Phase 1b/2a Study Combining LY2157299 with Standard Temozolomide-based Radiochemotherapy in Patients with Newly Diagnosed Malignant Glioma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b: Recommended Dose for Phase 2a Portion : Maximum Tolerated Dose (MTD)

Primary: Phase 1b: Recommended Dose for Phase 2a Portion : Maximum Tolerated Dose (MTD)

Secondary: Phase 2a: Relationship of Change in Response Biomarkers to Clinical Benefit (Overall Survival (OS) of Change in Biomarkers)

Secondary: Phase 2a: Relationship of Change in Response Biomarkers to Clinical Benefit (Overall Survival (OS) of Change in Biomarkers)

Secondary: Phase 1b: Pharmacokinetics (PK) - Maximum Observed Drug Concentration at Steady (Cmax ss)

Secondary: Phase 1b: Pharmacokinetics (PK) - Maximum Observed Drug Concentration at Steady (Cmax ss)

Secondary: Phase 1b: PK - Time of Maximum Observed Drug Concentration at Steady State (Tmax ss)

Secondary: Phase 1b: PK - Time of Maximum Observed Drug Concentration at Steady State (Tmax ss)

Secondary: Phase 1b: PK - Area Under the Concentration-Time Curve at Steady State From Time Zero to Infinity (AUC[0-∞],ss)

Secondary: Phase 1b: PK - Area Under the Concentration-Time Curve at Steady State From Time Zero to Infinity (AUC[0-∞],ss)

Secondary: Phase 1b: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR])

Secondary: Phase 1b: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR])

Secondary: Phase 2a: Percentage Overall Survival at 12 Months

Secondary: Phase 2a: Percentage Overall Survival at 12 Months

Secondary: Phase 2a: Overall Survival

Secondary: Phase 2a: Overall Survival

Secondary: Phase 2a: Progression Free Survival (PFS)

Secondary: Phase 2a: Progression Free Survival (PFS)

Secondary: Phase 2a: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR])

Secondary: Phase 2a: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR])

Secondary: Phase 2a: Duration of tumor Response

Secondary: Phase 2a: Duration of tumor Response

Secondary: Phase 2a: Time to Treatment Failure

Secondary: Phase 2a: Time to Treatment Failure

Secondary: Phase 2a: Change from baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) - Brain Tumor Symptoms, Core Symptoms, Interference Symptoms

Secondary: Phase 2a: Change from baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) - Brain Tumor Symptoms, Core Symptoms, Interference Symptoms

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
Phase 1b/2a Study Combining LY2157299 with Standard Temozolomide-based Radiochemotherapy in Patients with Newly Diagnosed Malignant Glioma