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Clinical Trial Results:
A Phase 1b/2 Study Assessing Safety and Anti-tumor Activity of AMG 820 in Combination With Pembrolizumab in Select Advanced Solid Tumors

Summary
EudraCT number	2016-001080-36
Trial protocol	BE DE ES
Global end of trial date	17 May 2019

Results information
Results version number	v1(current)
This version publication date	30 May 2020
First version publication date	30 May 2020
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

20150195

ISRCTN number

US NCT number

NCT02713529

WHO universal trial number (UTN)

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320-1799

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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

17 May 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 May 2019

Was the trial ended prematurely?

Main objective of the trial

- Evaluate the safety and tolerability of AMG 820 administered in combination with pembrolizumab in subjects with select advanced solid tumors - Evaluate the objective response rate (ORR) of AMG 820 and pembrolizumab combination as per irRECIST in subjects with select advanced solid tumors

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and Food and Drug Administration (FDA) regulations, and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.

Background therapy

Evidence for comparator

Actual start date of recruitment

14 Apr 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 57

Country: Number of subjects enrolled

Spain: 21

Country: Number of subjects enrolled

Australia: 16

Country: Number of subjects enrolled

Canada: 11

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

Germany: 5

Worldwide total number of subjects

117

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

This study was conducted at 15 centers in Australia, Canada, United States of America, and Europe.

Screening details

Part 1 was a phase Ib safety study comprised of two cohorts. Part 2 was a phase 2 safety and efficacy study comprised of 5 groups.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg

Arm description

Part 1 Cohort 2 includes participants with advanced solid tumors who were treated with 1100 mg AMG 820 plus 200 mg pembrolizumab (Pem) every three weeks (Q3W) to determine safety. Participants could be treated up to 24 months if treatment was tolerable and clinical benefit was observed.

Arm type

Experimental

Investigational medicinal product name

AMG 820

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1100 mg administered intravenously (IV) every third week.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Keytruda

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg

Arm description

Part 1 Cohort 1 includes participants with advanced solid tumors who were treated with 1400 mg AMG 820 plus 200 mg pembrolizumab (Pem) every three weeks (Q3W) to determine safety. Participants could be treated up to 24 months if treatment was tolerable and clinical benefit was observed. If >= 3 participants had dose limiting toxicities (DLTs), a second cohort was created with a lower AMG 820 dose + Pem 200 mg.

Arm type

Experimental

Investigational medicinal product name

AMG 820

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1400 mg administered intravenously (IV) every third week.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Keytruda

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

Part 2, Group 1: CRC MMR-proficient

Arm description

Group 1 is comprised of participants with colorectal cancer (CRC) who are proficient in mismatch repair genes (MMR). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

Arm type

Experimental

Investigational medicinal product name

AMG 820

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1100 mg administered intravenously (IV) every third week.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Keytruda

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

Part 2, Group 2: Pancreatic Cancer

Arm description

Group 2 is comprised of participants with advanced pancreatic cancer who are naïve to anti programmed-death 1 (PD-1), anti PD-ligand 1 (PD-L1), colony stimulating factor 1 (CSF-1) and colony stimulating factor 1 receptor (CSF-1R) therapies. AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

Arm type

Experimental

Investigational medicinal product name

AMG 820

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1100 mg administered intravenously (IV) every third week.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Keytruda

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

Part 2, Group 3: NSCLC PD-L1 Low, Naïve

Arm description

Group 3 is comprised of participants with non-small cell lung cancer (NSCLC) who have low (< 50%) tumor PD-L1- expression and are naïve to anti-PD-1/PD-L1/CSF-1/CSF-1R agents. AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

Arm type

Experimental

Investigational medicinal product name

AMG 820

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1100 mg administered intravenously (IV) every third week.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Keytruda

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low

Arm description

Group 4a is comprised of participants who did not respond to or who relapsed during monotherapy with anti-PD-1/PD-L1 agents and are anti-CSF-1/CSF-1R naïve. These participants have low PD-L1 tumor expression (<50%). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

Arm type

Experimental

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Keytruda

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

Investigational medicinal product name

AMG 820

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1100 mg administered intravenously (IV) every third week.

Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High

Arm description

Group 4b is comprised of participants who did not respond to or who relapsed during monotherapy with anti-PD-1/PD-L1 agents and are anti-CSF-1/CSF-1R naïve. These participants have high PD-L1 tumor expression (>=50%). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

Arm type

Experimental

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Keytruda

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

Investigational medicinal product name

AMG 820

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1100 mg administered intravenously (IV) every third week.

Number of subjects in period 1	Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg	Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg	Part 2, Group 1: CRC MMR-proficient	Part 2, Group 2: Pancreatic Cancer	Part 2, Group 3: NSCLC PD-L1 Low, Naïve	Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low	Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
Started	8	7	42	31	4	19	6
Completed	1	3	11	2	1	5	2
Not completed	7	4	31	29	3	14	4
Adverse event, serious fatal	3	3	26	27	3	13	3
Consent withdrawn by subject	3	1	4	2	-	1	1
Lost to follow-up	1	-	1	-	-	-	-

Baseline characteristics

Top of page

Reporting group title

Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg

Reporting group description

Reporting group title

Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg

Reporting group description

Reporting group title

Part 2, Group 1: CRC MMR-proficient

Reporting group description

Reporting group title

Part 2, Group 2: Pancreatic Cancer

Reporting group description

Reporting group title

Part 2, Group 3: NSCLC PD-L1 Low, Naïve

Reporting group description

Reporting group title

Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low

Reporting group description

Reporting group title

Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High

Reporting group description

Reporting group values	Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg	Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg	Part 2, Group 1: CRC MMR-proficient	Part 2, Group 2: Pancreatic Cancer	Part 2, Group 3: NSCLC PD-L1 Low, Naïve	Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low	Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High	Total
Number of subjects	8	7	42	31	4	19	6	117
Age Categorical
Units: participants
18-64 years	2	6	24	18	3	7	4	64
65-74 years	6	1	15	10	1	6	2	41
75-84 years	0	0	3	3	0	5	0	11
>=85 years	0	0	0	0	0	1	0	1
Sex: Female, Male
Units: participants
Female	5	3	16	14	1	1	3	43
Male	3	4	26	17	3	18	3	74
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	1	3	1	0	0	0	5
Not Hispanic or Latino	8	6	36	29	4	19	6	108
Unknown or Not Reported	0	0	3	1	0	0	0	4
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0
Asian	0	1	1	3	0	0	0	5
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0
Black or African American	0	0	0	1	0	2	1	4
White	8	5	39	26	4	17	5	104
More than one race	0	0	0	0	0	0	0	0
Unknown or Not Reported	0	1	2	1	0	0	0	4
Eastern Cooperative Oncology Group (ECOG) Performance Status
A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self care, unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
Units: Subjects
Grade 0	6	4	19	7	1	4	2	43
Grade 1	2	3	23	24	3	15	4	74
Grade 2	0	0	0	0	0	0	0	0
Grade 3	0	0	0	0	0	0	0	0
Grade 4	0	0	0	0	0	0	0	0
Grade 5	0	0	0	0	0	0	0	0
Number of Prior Line of Therapy
Units: Subjects
0 therapies	0	0	0	0	0	0	0	0
1 therapy	0	0	2	3	3	1	0	9
2 therapies	1	1	9	13	1	7	3	35
3 therapies	4	3	11	8	0	7	3	36
4 therapies	1	1	10	5	0	1	0	18
5 therapies	2	2	10	2	0	3	0	19
>5 therapies	0	0	0	0	0	0	0	0
Disease Stage at Screening
There are five stages of cancer: stage 0 (or, carcinoma in situ), stage I, stage II, stage III, and stage IV. Lower stages indicate that the disease is more localized, or contained, whereas higher stages refer to cancers that have spread into other areas of the body.
Units: Subjects
Stage I	1	1	0	0	0	0	0	2
Stage II	1	0	3	3	1	1	0	9
Stage III	0	0	4	2	0	2	1	9
Stage IV	6	6	35	26	3	16	5	97

End points

Top of page

Reporting group title

Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg

Reporting group description

Reporting group title

Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg

Reporting group description

Reporting group title

Part 2, Group 1: CRC MMR-proficient

Reporting group description

Reporting group title

Part 2, Group 2: Pancreatic Cancer

Reporting group description

Reporting group title

Part 2, Group 3: NSCLC PD-L1 Low, Naïve

Reporting group description

Reporting group title

Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low

Reporting group description

Reporting group title

Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High

Reporting group description

Subject analysis set title

Part 1: AMG 820 + Pem 200 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Part 1 Cohorts 1 + 2 combined. Participants with advanced solid tumors were treated with 1400 mg or 1100 mg AMG 820 plus 200 mg pembrolizumab (Pem) every three weeks (Q3W) to determine safety. Participants could be treated up to 24 months if treatment was tolerable and clinical benefit was observed.

Subject analysis set title

AMG 820 1100 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Includes participants from all treatment arms that were administered AMG 820 1100 mg.

Subject analysis set title

AMG 820 1400 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Includes participants from all treatment arms who were administered AMG 820 1400 mg

Primary: Participants with Dose Limiting Toxicities (DLT)

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End point title

Participants with Dose Limiting Toxicities (DLT) ^[1]

End point description

DLTs were evaluated by the Dose Level Review Team (DLRT). A DLT was defined as any grade >=3 adverse event occurring during a DLT time window (21 day period from the initial administration of AMG 820 and pembrolizumab in combination), and if judged by the investigator to be related to the administration of AMG 820 and/or pembrolizumab.

End point type

Primary

End point timeframe

The DLT evaluation period was Day 1 to Day 21

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: The statistical reporting of the safety outcomes was entirely descriptive, with no formal statistical testing performed.

End point values	Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg	Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg	Part 2, Group 1: CRC MMR-proficient	Part 2, Group 2: Pancreatic Cancer	Part 2, Group 3: NSCLC PD-L1 Low, Naïve	Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low	Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
Number of subjects analysed	8	7	41	31	4	19	6
Units: participants
Participants with treatment emergent DLTs	0	1	3	2	0	1	0
DLT: Autoimmune pancreatitis	0	1	0	0	0	0	0
DLT: Autoimmune hepatitis	0	1	0	0	0	0	0
DLT: Cholecystitis	0	1	0	0	0	0	0
DLT: Electrolyte imbalance	0	1	0	0	0	0	0
DLT: Fatigue	0	0	1	0	0	0	0
DLT: Aspartate aminotransferase increased	0	0	1	1	0	0	0
DLT: Lipase increased	0	0	0	0	0	1	0
DLT: Epilepsy	0	0	0	1	0	0	0
DLT: Rash generalised	0	0	1	0	0	0	0
DLT: Rash maculo-papular	0	0	1	0	0	0	0

No statistical analyses for this end point

Primary: Participants with Treatment -Emergent Adverse Events (TEAEs)

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End point title

Participants with Treatment -Emergent Adverse Events (TEAEs) ^[2]

End point description

TEAEs include any adverse event starting on or after the first dose of AMG 820 or pembrolizumab. Relation to study drugs was determined by the investigator. Adverse events (AEs) were graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, where Grade 1 = mild AE, Grade 2 = moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. Errors in the case report form design resulted in investigators misunderstanding the CTCAE definition for severity grade 5. Therefore, data are not reported for severity grade 5 (9999=not available). Readers are referred to the ‘Fatal TEAE’ line in the table below for counts of participants who died during the TEAE timeframe.

End point type

Primary

End point timeframe

Day 1 up to 207 days for Part 1 and Day 1 up to 572 days for Part 2

Notes
[2] - 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: The statistical reporting of the safety outcomes was entirely descriptive, with no formal statistical testing performed.

End point values	Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg	Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg	Part 2, Group 1: CRC MMR-proficient	Part 2, Group 2: Pancreatic Cancer	Part 2, Group 3: NSCLC PD-L1 Low, Naïve	Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low	Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
Number of subjects analysed	8	7	41	31	4	19	6
Units: participants
number (not applicable)
>=1 TEAE	8	7	41	31	4	19	6
Grade >=3	7	7	40	30	4	19	6
Grade >=4	2	4	24	26	2	12	4
Grade >=5	9999	9999	9999	9999	9999	9999	9999
Serious AE	5	2	31	23	3	11	5
Leading to interruption of AMG 820	4	3	23	7	1	7	2
Leading to discontinuation AMG 820	0	0	6	5	2	1	3
---- SAE leading to d/c AMG 820	0	0	4	4	1	0	2
----Non-serious AE leading to d/c AMG 820	0	0	2	1	1	1	1
Leading to discontinuation of PEM	1	0	7	5	2	1	3
---- SAE leading to d/c PEM	0	0	4	4	1	0	2
----Non-serious AE leading to d/c PEM	1	0	3	1	1	1	1
Fatal TEAE	1	0	4	3	0	3	2
TEAE related to study procedure/activity	0	1	11	5	0	3	1

No statistical analyses for this end point

Primary: Participants with Treatment -Emergent Adverse Events (TEAEs) Related to AMG 820 Treatment

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End point title

Participants with Treatment -Emergent Adverse Events (TEAEs) Related to AMG 820 Treatment ^[3]

End point description

End point type

Primary

End point timeframe

Day 1 up to 207 days for Part 1; Day 1 up to 572 days for Part 2

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: The statistical reporting of the safety outcomes was entirely descriptive, with no formal statistical testing performed.

End point values	Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg	Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg	Part 2, Group 1: CRC MMR-proficient	Part 2, Group 2: Pancreatic Cancer	Part 2, Group 3: NSCLC PD-L1 Low, Naïve	Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low	Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
Number of subjects analysed	8	7	41	31	4	19	6
Units: participants
>=1 TEAE	5	7	41	25	4	14	6
Grade >=3	3	5	28	11	1	10	6
Grade >=4	1	1	5	5	0	2	2
Grade >=5	9999	9999	9999	9999	9999	9999	9999
Serious AE	2	2	12	4	0	3	3
Leading to interruption of AMG 820	2	3	16	7	0	5	2
Leading to discontinuation AMG 820	0	0	3	3	1	0	3
---- SAE leading to d/c AMG 820	0	0	3	2	0	0	2
----Non-serious AE leading to d/c AMG 820	0	0	0	1	1	0	1
Leading to discontinuation of PEM	0	0	4	3	1	0	3
---- SAE leading to d/c PEM	0	0	3	2	0	0	2
----Non-serious AE leading to d/c PEM	0	0	1	1	1	0	1
Fatal TEAE	0	0	1	0	0	0	1
TEAE related to study procedure/activity	0	0	8	2	0	3	1

No statistical analyses for this end point

Primary: Participants with Treatment -Emergent Adverse Events (TEAEs) Related to Pembrolizumab Treatment

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End point title

Participants with Treatment -Emergent Adverse Events (TEAEs) Related to Pembrolizumab Treatment ^[4]

End point description

End point type

Primary

End point timeframe

Day 1 up to 207 days for Part 1 and Day 1 up to 572 days for Part 2

Notes
[4] - 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: The statistical reporting of the safety outcomes was entirely descriptive, with no formal statistical testing performed.

End point values	Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg	Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg	Part 2, Group 1: CRC MMR-proficient	Part 2, Group 2: Pancreatic Cancer	Part 2, Group 3: NSCLC PD-L1 Low, Naïve	Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low	Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
Number of subjects analysed	8	7	41	31	4	19	6
Units: participants
>=1 TEAE	5	7	39	24	4	13	6
Grade >=3	2	5	29	9	1	10	4
Grade >=4	1	1	5	4	0	2	2
Grade >=5	9999	9999	9999	9999	9999	9999	9999
Serious AE	2	2	16	5	0	3	4
Leading to interruption of PEM	1	3	15	6	0	5	2
Leading to discontinuation AMG 820	0	0	4	2	1	1	3
---- SAE leading to d/c AMG 820	0	0	3	1	0	0	2
----Non-serious AE leading to d/c AMG 820	0	0	1	1	1	1	1
Leading to discontinuation of PEM	0	0	5	2	1	1	3
---- SAE leading to d/c PEM	0	0	3	1	0	0	2
----Non-serious AE leading to d/c PEM	0	0	2	1	1	1	1
Fatal TEAE	0	0	1	0	0	0	1
TEAE related to study procedure/activity	0	0	9	3	0	2	1

No statistical analyses for this end point

Primary: Objective Response Rate (ORR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST)

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End point title

Objective Response Rate (ORR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) ^[5] ^[6]

End point description

ORR was defined as the percentage of participants with a best overall response of complete response or partial response assessed by the investigator using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Response was based on the size of tumors assessed by computed tomography (CT) or magnetic resonance imaging (MRI). During treatment radiographic imaging was performed at Week 10 and repeated at least every 10 weeks until disease progression. Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. Confirmation by a consecutive assessment at least 4 weeks after first documentation required.

End point type

Primary

End point timeframe

Baseline: Day -28; Treatment: up to Month 13.7

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 formal statistical testing was performed comparing groups of participants with different diagnoses.
[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: Part 1 dose finding cohorts were combined when reporting results for this outcome.

End point values	Part 2, Group 1: CRC MMR-proficient	Part 2, Group 2: Pancreatic Cancer	Part 2, Group 3: NSCLC PD-L1 Low, Naïve	Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low	Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High	Part 1: AMG 820 + Pem 200 mg
Number of subjects analysed	41	31	4	19	6	15
Units: percentage of participants
number (confidence interval 95%)	4.9 (0.60 to 16.53)	0.0 (0.0 to 0.0)	0.0 (0.0 to 0.0)	5.3 (0.13 to 26.03)	0.0 (0.0 to 0.0)	0.0 (0.00 to 0.00)

No statistical analyses for this end point

Secondary: Time to Response (TTR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) For Participants Who Responded

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End point title

Time to Response (TTR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) For Participants Who Responded ^[7]

End point description

Time to response was defined as the time from first dose of AMG 820 until first documented complete or partial response per irRECIST divided by 365.25 days/12.

End point type

Secondary

End point timeframe

Day 1 up to Month 16 (max time to censoring)

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: Part 1 dose finding cohorts were combined when reporting results for this outcome.

End point values	Part 2, Group 1: CRC MMR-proficient	Part 2, Group 2: Pancreatic Cancer	Part 2, Group 3: NSCLC PD-L1 Low, Naïve	Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low	Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High	Part 1: AMG 820 + Pem 200 mg
Number of subjects analysed	2	0 ^[8]	0 ^[9]	1	0 ^[10]	0 ^[11]
Units: month
arithmetic mean (full range (min-max))	2.1587 (2.004 to 2.168)	( to )	( to )	2.0698 (2.0698 to 2.0698)	( to )	( to )

Notes
[8] - No responders
[9] - No responders
[10] - No responders
[11] - No responders

No statistical analyses for this end point

Secondary: Time to Progression (TTP) for Participants Who had Progressive Disease

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End point title

Time to Progression (TTP) for Participants Who had Progressive Disease ^[12]

End point description

Time to progression was defined as the time from first dose of AMG 820 until first documented progressive disease per irRECIST divided by 365.25 days/12.

End point type

Secondary

End point timeframe

Day 1 up to 14.4 months (max time to censoring)

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: Part 1 dose finding cohorts were combined when reporting results for this outcome.

End point values	Part 2, Group 1: CRC MMR-proficient	Part 2, Group 2: Pancreatic Cancer	Part 2, Group 3: NSCLC PD-L1 Low, Naïve	Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low	Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High	Part 1: AMG 820 + Pem 200 mg
Number of subjects analysed	29	13	3	8	4	10
Units: month
arithmetic mean (full range (min-max))	3.0691 (0.559 to 8.411)	2.3878 (0.296 to 4.698)	4.6762 (2.070 to 6.604)	6.0863 (1.150 to 11.992)	7.7864 (1.938 to 13.667)	2.1865 (0.460 to 5.552)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimates for Overall Survival (OS) at Month 6 and Month 12

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End point title

Kaplan-Meier Estimates for Overall Survival (OS) at Month 6 and Month 12 ^[13]

End point description

Overall survival time was calculated as the number of days from the first administration of AMG 820 to date of death or censoring divided by (365.25/12). Data are reported as the percentage of participants who were alive at Month 6 and Month 12.

End point type

Secondary

End point timeframe

Day 1 up to Month 6 or Month 12

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: Part 1 dose finding cohorts were combined when reporting results for this outcome.

End point values	Part 2, Group 1: CRC MMR-proficient	Part 2, Group 2: Pancreatic Cancer	Part 2, Group 3: NSCLC PD-L1 Low, Naïve	Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low	Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High	Part 1: AMG 820 + Pem 200 mg
Number of subjects analysed	41 ^[14]	31 ^[15]	4 ^[16]	19 ^[17]	6 ^[18]	15 ^[19]
Units: percentage of participants
number (confidence interval 90%)
Month 6	53.915 (40.00 to 63.93)	16.705 (7.40 to 29.24)	75.000 (22.34 to 94.63)	52.105 (31.91 to 68.93)	41.667 (9.26 to 72.47)	59.077 (32.25 to 78.28)
Month 12	38.963 (25.77 to 51.94)	8.353 (2.22 to 19.81)	25.00 (2.08 to 60.89)	34.737 (17.37 to 52.79)	41.667 (9.26 to 72.47)	47.262 (21.19 to 69.63)

Notes
[14] - Month 6; 19 subjects at risk Month 12: 10 subjects at risk
[15] - Month 6; 5 subjects at risk Month 12: 2 subjects at risk
[16] - Month 6; 3 subjects at risk Month 12: 0 subjects at risk
[17] - Month 6; 9 subjects at risk Month 12: 6 subjects at risk
[18] - Month 6; 2 subjects at risk Month 12: 2 subjects at risk
[19] - Month 6; 5 subjects at risk Month 12: 2 subjects at risk

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimates for Progression-Free Survival (PFS) as per irRECIST at Month 6 and Month 12

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End point title

Kaplan-Meier Estimates for Progression-Free Survival (PFS) as per irRECIST at Month 6 and Month 12 ^[20]

End point description

Progression-free survival time was calculated as the number of days from the first administration of AMG 820 to date of progressive disease or death or censoring divided by (365.25/12). Data are reported as the percentage of participants who were alive and progression-free at Month 6 and Month 12.

End point type

Secondary

End point timeframe

Day 1 up to Month 6 or Month 12

Notes
[20] - 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: Part 1 dose finding cohorts were combined when reporting results for this outcome.

End point values	Part 2, Group 1: CRC MMR-proficient	Part 2, Group 2: Pancreatic Cancer	Part 2, Group 3: NSCLC PD-L1 Low, Naïve	Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low	Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High	Part 1: AMG 820 + Pem 200 mg
Number of subjects analysed	41 ^[21]	31 ^[22]	4 ^[23]	19 ^[24]	6 ^[25]	15 ^[26]
Units: percentage of participants
number (confidence interval 90%)
Month 6	13.490 (5.99 to 24.04)	0.000 (0.00 to 0.00)	25.000 (2.08 to 60.89)	26.471 (10.67 to 45.41)	33.333 (7.37 to 62.95)	10.476 (1.23 to 31.40)
Month 12	5.396 (1.36 to 13.77)	0.000 (0.00 to 0.00)	0.000 (0.00 to 0.00)	6.618 (0.77 to 21.97)	33.333 (7.37 to 62.95)	0.000 (0.00 to 0.00)

Notes
[21] - Month 6: 5 subjects at risk Month 12: 1 subject at risk
[22] - Month 6: 0 subjects at risk Month 12: 0 subject at risk
[23] - Month 6: 1 subject at risk Month 12: 0 subject at risk
[24] - Month 6: 4 subjects at risk Month 12: 1 subject at risk
[25] - Month 6: 2 subjects at risk Month 12: 2 subjects at risk
[26] - Month 6: 1 subject at risk Month 12: 0 subject at risk

No statistical analyses for this end point

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Time of Maximum Observed Concentration (tmax) During Treatment Cycles 1 + 2

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End point title

AMG 820 Pharmacokinetic Parameter by Dose Group: Time of Maximum Observed Concentration (tmax) During Treatment Cycles 1 + 2

End point description

End point type

Secondary

End point timeframe

Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36

End point values	AMG 820 1100 mg	AMG 820 1400 mg
Number of subjects analysed	97	18
Units: hour
median (full range (min-max))
Cycle 1 (n=97, 18)	2.0 (1.0 to 170)	2.0 (1.0 to 7.0)
Cycle 2 (n=71, 10)	3.00 (1.00 to 25.0)	2.00 (1.00 to 25.0)

No statistical analyses for this end point

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Maximum Observed Drug Concentration (Cmax) During Treatment Cycles 1 + 2

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End point title

AMG 820 Pharmacokinetic Parameter by Dose Group: Maximum Observed Drug Concentration (Cmax) During Treatment Cycles 1 + 2

End point description

End point type

Secondary

End point timeframe

End point values	AMG 820 1100 mg	AMG 820 1400 mg
Number of subjects analysed	97	18
Units: ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n=97, 18)	331 ± 27	485 ± 23
Cycle 2 (n=71, 10)	363 ± 32	536 ± 21

No statistical analyses for this end point

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve last (AUClast) During Treatment Cycles 1 + 2

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End point title

AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve last (AUClast) During Treatment Cycles 1 + 2

End point description

AUClast is the area under the serum concentration-time curve from time zero to time of last quantifiable concentration.

End point type

Secondary

End point timeframe

End point values	AMG 820 1100 mg	AMG 820 1400 mg
Number of subjects analysed	97	18
Units: hr*ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n=97, 18)	55100 ± 37	80400 ± 33
Cycle 2 (n=71, 10)	55200 ± 38	73500 ± 45

No statistical analyses for this end point

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve Over the Dose Interval (AUCtau) During Treatment Cycles 1 + 2

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End point title

AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve Over the Dose Interval (AUCtau) During Treatment Cycles 1 + 2

End point description

AUCtau is the area under the serum concentration-time curve over the dose interval tau, with tau equal to 21 days.

End point type

Secondary

End point timeframe

End point values	AMG 820 1100 mg	AMG 820 1400 mg
Number of subjects analysed	97	18
Units: hr*ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n=97, 18)	59300 ± 33	90000 ± 29
Cycle 2 (n=68, 9)	75400 ± 35	114000 ± 31

No statistical analyses for this end point

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Minimum Observed Drug Concentration (Cmin) During Treatment Cycles 1 + 2

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End point title

AMG 820 Pharmacokinetic Parameter by Dose Group: Minimum Observed Drug Concentration (Cmin) During Treatment Cycles 1 + 2

End point description

End point type

Secondary

End point timeframe

End point values	AMG 820 1100 mg	AMG 820 1400 mg
Number of subjects analysed	70	10
Units: ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n=70, 10)	49.9 ± 51	90.9 ± 35
Cycle 2 (n=48, 3)	78.7 ± 66	199 ± 34

No statistical analyses for this end point

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Terminal Elimination Half-life (t1/2z) During Treatment Cycles 1 + 2

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End point title

AMG 820 Pharmacokinetic Parameter by Dose Group: Terminal Elimination Half-life (t1/2z) During Treatment Cycles 1 + 2

End point description

End point type

Secondary

End point timeframe

End point values	AMG 820 1100 mg	AMG 820 1400 mg
Number of subjects analysed	46	7
Units: hour
geometric mean (geometric coefficient of variation)
Cycle 1 (n=46, 7)	217 ± 26	214 ± 24
Cycle 2 (n=7, not reported)	170 ± 16	9999 ± 9999

No statistical analyses for this end point

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Volume of Distribution (Vz) During Treatment Cycles 1 + 2

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End point title

AMG 820 Pharmacokinetic Parameter by Dose Group: Volume of Distribution (Vz) During Treatment Cycles 1 + 2

End point description

Volume of distribution observed at terminal phase after intravenous dosing.

End point type

Secondary

End point timeframe

End point values	AMG 820 1100 mg	AMG 820 1400 mg
Number of subjects analysed	46	7
Units: liter
geometric mean (geometric coefficient of variation)
Cycle 1 (n=46, 7)	5200 ± 35	4110 ± 25
Cycle 2 (n=7, not reported)	4560 ± 21	9999 ± 9999

No statistical analyses for this end point

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Drug Clearance (CL) During Treatment Cycles 1 + 2

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End point title

AMG 820 Pharmacokinetic Parameter by Dose Group: Drug Clearance (CL) During Treatment Cycles 1 + 2

End point description

Drug clearance observed after intravenous dosing.

End point type

Secondary

End point timeframe

End point values	AMG 820 1100 mg	AMG 820 1400 mg
Number of subjects analysed	46	7
Units: liter/hour
geometric mean (geometric coefficient of variation)
Cycle 1 (n=46, 7)	16.6 ± 37	13.3 ± 33
Cycle 2 (n=7, not reported)	18.6 ± 30	9999 ± 9999

No statistical analyses for this end point

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Accumulation Ratio (AR)

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End point title

AMG 820 Pharmacokinetic Parameter by Dose Group: Accumulation Ratio (AR)

End point description

Accumulation ratio is AUCtau following administration in Cycle 2 / AUCtau after administration in Cycle 1

End point type

Secondary

End point timeframe

End point values	AMG 820 1100 mg	AMG 820 1400 mg
Number of subjects analysed	68	9
Units: ratio
geometric mean (geometric coefficient of variation)	1.23 ± 18	1.25 ± 16

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

The TEAE timeframe was Day 1 up to 207 days for Part 1 and Day 1 up to 572 days for Part 2. The median time frame is 122 days..

Adverse event reporting additional description

All adverse events (AEs) and disease related events (DREs) are integrated in the summaries.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

AMG 820 1400 MG

Reporting group description

Includes participants from all treatment arms that were administered AMG 820 1400 mg.

Reporting group title

AMG 820 1100 MG

Reporting group description

Includes participants from all treatment arms that were administered AMG 820 1100 mg.

Serious adverse events	AMG 820 1400 MG	AMG 820 1100 MG
Total subjects affected by serious adverse events
subjects affected / exposed	10 / 18 (55.56%)	70 / 98 (71.43%)
number of deaths (all causes)	1	12
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colorectal cancer
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Colorectal cancer metastatic
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant pleural effusion
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Non-small cell lung cancer metastatic
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Pancreatic carcinoma metastatic
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour flare
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Tumour haemorrhage
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 18 (0.00%)	3 / 98 (3.06%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	2 / 18 (11.11%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 18 (0.00%)	8 / 98 (8.16%)
occurrences causally related to treatment / all	0 / 0	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 18 (0.00%)	3 / 98 (3.06%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngeal inflammation
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 18 (0.00%)	4 / 98 (4.08%)
occurrences causally related to treatment / all	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 18 (5.56%)	3 / 98 (3.06%)
occurrences causally related to treatment / all	2 / 2	3 / 3
deaths causally related to treatment / all	1 / 1	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 18 (0.00%)	3 / 98 (3.06%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial flutter
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure congestive
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebellar infarction
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Dizziness
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Embolic cerebral infarction
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 18 (0.00%)	3 / 98 (3.06%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Periorbital oedema
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uveitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 18 (11.11%)	3 / 98 (3.06%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Autoimmune pancreatitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal perforation
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Enterovesical fistula
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Ileus
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Proctalgia
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Vomiting
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	0 / 18 (0.00%)	3 / 98 (3.06%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary colic
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune-mediated hepatitis
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Erythema nodosum
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash generalised
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 18 (0.00%)	3 / 98 (3.06%)
occurrences causally related to treatment / all	0 / 0	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nephritis
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal haemorrhage
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 18 (0.00%)	3 / 98 (3.06%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis staphylococcal
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic abscess
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 18 (11.11%)	3 / 98 (3.06%)
occurrences causally related to treatment / all	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 18 (0.00%)	5 / 98 (5.10%)
occurrences causally related to treatment / all	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 18 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	AMG 820 1400 MG	AMG 820 1100 MG
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 18 (100.00%)	97 / 98 (98.98%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer metastatic
subjects affected / exposed	3 / 18 (16.67%)	1 / 98 (1.02%)
occurrences all number	3	1
Colorectal cancer metastatic
subjects affected / exposed	1 / 18 (5.56%)	4 / 98 (4.08%)
occurrences all number	1	4
Non-small cell lung cancer metastatic
subjects affected / exposed	1 / 18 (5.56%)	2 / 98 (2.04%)
occurrences all number	1	2
Pancreatic carcinoma
subjects affected / exposed	2 / 18 (11.11%)	6 / 98 (6.12%)
occurrences all number	2	6
Pancreatic carcinoma metastatic
subjects affected / exposed	4 / 18 (22.22%)	9 / 98 (9.18%)
occurrences all number	4	9
Rectal cancer
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
Tumour haemorrhage
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 18 (5.56%)	2 / 98 (2.04%)
occurrences all number	1	2
Embolism
subjects affected / exposed	1 / 18 (5.56%)	2 / 98 (2.04%)
occurrences all number	1	2
Hypertension
subjects affected / exposed	4 / 18 (22.22%)	16 / 98 (16.33%)
occurrences all number	4	25
Hypotension
subjects affected / exposed	0 / 18 (0.00%)	5 / 98 (5.10%)
occurrences all number	0	5
Venous thrombosis
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 18 (0.00%)	8 / 98 (8.16%)
occurrences all number	0	9
Chills
subjects affected / exposed	3 / 18 (16.67%)	11 / 98 (11.22%)
occurrences all number	3	12
Face oedema
subjects affected / exposed	5 / 18 (27.78%)	14 / 98 (14.29%)
occurrences all number	10	20
Fatigue
subjects affected / exposed	10 / 18 (55.56%)	52 / 98 (53.06%)
occurrences all number	12	78
Hyperthermia malignant
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Oedema
subjects affected / exposed	1 / 18 (5.56%)	4 / 98 (4.08%)
occurrences all number	1	4
Oedema peripheral
subjects affected / exposed	2 / 18 (11.11%)	10 / 98 (10.20%)
occurrences all number	2	12
Pain
subjects affected / exposed	0 / 18 (0.00%)	6 / 98 (6.12%)
occurrences all number	0	6
Pyrexia
subjects affected / exposed	3 / 18 (16.67%)	25 / 98 (25.51%)
occurrences all number	4	34
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 18 (5.56%)	19 / 98 (19.39%)
occurrences all number	1	23
Dyspnoea
subjects affected / exposed	3 / 18 (16.67%)	22 / 98 (22.45%)
occurrences all number	3	26
Hiccups
subjects affected / exposed	1 / 18 (5.56%)	2 / 98 (2.04%)
occurrences all number	1	2
Nasal congestion
subjects affected / exposed	1 / 18 (5.56%)	5 / 98 (5.10%)
occurrences all number	1	7
Oropharyngeal pain
subjects affected / exposed	1 / 18 (5.56%)	3 / 98 (3.06%)
occurrences all number	1	3
Pleural effusion
subjects affected / exposed	0 / 18 (0.00%)	9 / 98 (9.18%)
occurrences all number	0	10
Psychiatric disorders
Anxiety
subjects affected / exposed	2 / 18 (11.11%)	5 / 98 (5.10%)
occurrences all number	2	5
Confusional state
subjects affected / exposed	1 / 18 (5.56%)	6 / 98 (6.12%)
occurrences all number	1	6
Insomnia
subjects affected / exposed	4 / 18 (22.22%)	4 / 98 (4.08%)
occurrences all number	4	4
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 18 (0.00%)	6 / 98 (6.12%)
occurrences all number	0	12
Alanine aminotransferase
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
Alanine aminotransferase increased
subjects affected / exposed	4 / 18 (22.22%)	21 / 98 (21.43%)
occurrences all number	4	28
Amylase increased
subjects affected / exposed	5 / 18 (27.78%)	19 / 98 (19.39%)
occurrences all number	5	35
Aspartate aminotransferase abnormal
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Aspartate aminotransferase increased
subjects affected / exposed	12 / 18 (66.67%)	58 / 98 (59.18%)
occurrences all number	20	110
Blood alkaline phosphatase increased
subjects affected / exposed	5 / 18 (27.78%)	13 / 98 (13.27%)
occurrences all number	13	18
Blood bilirubin increased
subjects affected / exposed	0 / 18 (0.00%)	5 / 98 (5.10%)
occurrences all number	0	11
Blood creatine phosphokinase increased
subjects affected / exposed	2 / 18 (11.11%)	1 / 98 (1.02%)
occurrences all number	2	1
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
International normalised ratio increased
subjects affected / exposed	0 / 18 (0.00%)	5 / 98 (5.10%)
occurrences all number	0	8
Lipase increased
subjects affected / exposed	5 / 18 (27.78%)	18 / 98 (18.37%)
occurrences all number	5	37
Liver function test abnormal
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Lymphocyte count decreased
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
Transaminases increased
subjects affected / exposed	0 / 18 (0.00%)	7 / 98 (7.14%)
occurrences all number	0	10
Troponin increased
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Weight decreased
subjects affected / exposed	1 / 18 (5.56%)	6 / 98 (6.12%)
occurrences all number	1	7
White blood cell count decreased
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
Cardiac disorders
Bradycardia
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
Nervous system disorders
Akathisia
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Aphasia
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
Dizziness
subjects affected / exposed	1 / 18 (5.56%)	6 / 98 (6.12%)
occurrences all number	1	7
Dysgeusia
subjects affected / exposed	0 / 18 (0.00%)	5 / 98 (5.10%)
occurrences all number	0	5
Facial paresis
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Headache
subjects affected / exposed	2 / 18 (11.11%)	11 / 98 (11.22%)
occurrences all number	2	15
Lethargy
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
Peripheral sensory neuropathy
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 18 (22.22%)	35 / 98 (35.71%)
occurrences all number	8	70
Eye disorders
Periorbital oedema
subjects affected / exposed	10 / 18 (55.56%)	38 / 98 (38.78%)
occurrences all number	13	46
Periorbital swelling
subjects affected / exposed	1 / 18 (5.56%)	2 / 98 (2.04%)
occurrences all number	1	4
Photophobia
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Uveitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Vision blurred
subjects affected / exposed	2 / 18 (11.11%)	2 / 98 (2.04%)
occurrences all number	2	2
Visual impairment
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 18 (5.56%)	6 / 98 (6.12%)
occurrences all number	1	6
Abdominal pain
subjects affected / exposed	6 / 18 (33.33%)	20 / 98 (20.41%)
occurrences all number	7	29
Ascites
subjects affected / exposed	0 / 18 (0.00%)	6 / 98 (6.12%)
occurrences all number	0	7
Constipation
subjects affected / exposed	9 / 18 (50.00%)	22 / 98 (22.45%)
occurrences all number	10	27
Diarrhoea
subjects affected / exposed	5 / 18 (27.78%)	23 / 98 (23.47%)
occurrences all number	7	36
Dry mouth
subjects affected / exposed	3 / 18 (16.67%)	8 / 98 (8.16%)
occurrences all number	3	8
Duodenal obstruction
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Dyspepsia
subjects affected / exposed	0 / 18 (0.00%)	5 / 98 (5.10%)
occurrences all number	0	6
Dysphagia
subjects affected / exposed	1 / 18 (5.56%)	3 / 98 (3.06%)
occurrences all number	1	3
Flatulence
subjects affected / exposed	1 / 18 (5.56%)	2 / 98 (2.04%)
occurrences all number	1	2
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 18 (5.56%)	2 / 98 (2.04%)
occurrences all number	1	2
Nausea
subjects affected / exposed	7 / 18 (38.89%)	26 / 98 (26.53%)
occurrences all number	8	32
Oral pain
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Proctalgia
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
Rectal haemorrhage
subjects affected / exposed	1 / 18 (5.56%)	2 / 98 (2.04%)
occurrences all number	1	2
Stomatitis
subjects affected / exposed	1 / 18 (5.56%)	3 / 98 (3.06%)
occurrences all number	1	3
Vomiting
subjects affected / exposed	5 / 18 (27.78%)	12 / 98 (12.24%)
occurrences all number	8	15
Hepatobiliary disorders
Hepatotoxicity
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	2	0
Portal vein thrombosis
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	0 / 18 (0.00%)	5 / 98 (5.10%)
occurrences all number	0	6
Photosensitivity reaction
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Pruritus
subjects affected / exposed	4 / 18 (22.22%)	19 / 98 (19.39%)
occurrences all number	7	26
Rash
subjects affected / exposed	2 / 18 (11.11%)	25 / 98 (25.51%)
occurrences all number	3	46
Rash maculo-papular
subjects affected / exposed	5 / 18 (27.78%)	14 / 98 (14.29%)
occurrences all number	8	26
Skin lesion
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Renal and urinary disorders
Bladder spasm
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Haematuria
subjects affected / exposed	1 / 18 (5.56%)	7 / 98 (7.14%)
occurrences all number	1	10
Nephrotic syndrome
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	2	0
Proteinuria
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
Urinary retention
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 18 (0.00%)	6 / 98 (6.12%)
occurrences all number	0	6
Parathyroid disorder
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 18 (11.11%)	9 / 98 (9.18%)
occurrences all number	2	9
Back pain
subjects affected / exposed	1 / 18 (5.56%)	10 / 98 (10.20%)
occurrences all number	3	10
Muscular weakness
subjects affected / exposed	0 / 18 (0.00%)	5 / 98 (5.10%)
occurrences all number	0	7
Musculoskeletal pain
subjects affected / exposed	0 / 18 (0.00%)	7 / 98 (7.14%)
occurrences all number	0	7
Myalgia
subjects affected / exposed	2 / 18 (11.11%)	2 / 98 (2.04%)
occurrences all number	2	2
Myopathy
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Infections and infestations
Bacteraemia
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Candida infection
subjects affected / exposed	0 / 18 (0.00%)	8 / 98 (8.16%)
occurrences all number	0	9
Conjunctivitis
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
Lower respiratory tract infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Lung infection
subjects affected / exposed	1 / 18 (5.56%)	3 / 98 (3.06%)
occurrences all number	1	5
Mucosal infection
subjects affected / exposed	2 / 18 (11.11%)	0 / 98 (0.00%)
occurrences all number	2	0
Oral candidiasis
subjects affected / exposed	0 / 18 (0.00%)	5 / 98 (5.10%)
occurrences all number	0	6
Skin infection
subjects affected / exposed	1 / 18 (5.56%)	2 / 98 (2.04%)
occurrences all number	1	2
Upper respiratory tract infection
subjects affected / exposed	0 / 18 (0.00%)	5 / 98 (5.10%)
occurrences all number	0	7
Urinary tract infection
subjects affected / exposed	0 / 18 (0.00%)	6 / 98 (6.12%)
occurrences all number	0	6
Viral infection
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	1	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	9 / 18 (50.00%)	22 / 98 (22.45%)
occurrences all number	11	29
Dehydration
subjects affected / exposed	1 / 18 (5.56%)	6 / 98 (6.12%)
occurrences all number	1	6
Hyperglycaemia
subjects affected / exposed	1 / 18 (5.56%)	4 / 98 (4.08%)
occurrences all number	1	7
Hyperlipasaemia
subjects affected / exposed	0 / 18 (0.00%)	5 / 98 (5.10%)
occurrences all number	0	12
Hyperuricaemia
subjects affected / exposed	1 / 18 (5.56%)	1 / 98 (1.02%)
occurrences all number	2	1
Hypoalbuminaemia
subjects affected / exposed	2 / 18 (11.11%)	11 / 98 (11.22%)
occurrences all number	2	12
Hypocalcaemia
subjects affected / exposed	1 / 18 (5.56%)	6 / 98 (6.12%)
occurrences all number	3	11
Hypokalaemia
subjects affected / exposed	3 / 18 (16.67%)	9 / 98 (9.18%)
occurrences all number	3	14
Hypomagnesaemia
subjects affected / exposed	0 / 18 (0.00%)	10 / 98 (10.20%)
occurrences all number	0	11
Hyponatraemia
subjects affected / exposed	2 / 18 (11.11%)	12 / 98 (12.24%)
occurrences all number	6	21
Hypophosphataemia
subjects affected / exposed	8 / 18 (44.44%)	18 / 98 (18.37%)
occurrences all number	17	30
Ketoacidosis
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0
Vitamin D deficiency
subjects affected / exposed	1 / 18 (5.56%)	0 / 98 (0.00%)
occurrences all number	1	0

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Were there any global substantial amendments to the protocol? Yes

03 Oct 2016

• Updated Safety Follow Up period from 30 days to 135 days after last study treatment throughout the protocol. • Added a Dose Rationale section for AMG 820 (Section 2.2.4) and corresponding Table of Contents entry. • Clarified important identified risks, important potential risks, and referred to most current IB for AMG 820 in Risk Assessment Section 2.3. • Added new exclusion criterion to exclude subjects with active infection within 2 weeks prior to study enrollment. • Added new exclusion criterion to exclude subjects who have received systemic immunostimulatory agents within 6 weeks or five half-lives, whichever is shorter, prior to first dose of study treatment (except anti PD-1/PD-L1 treatment if recruited into Group 4a or 4b). • Modified existing exclusion criteria to also exclude subjects with prior stem cell transplantation. • Modified existing exclusion criteria to also exclude subjects who have other signs or symptoms of clinical immune system suppression. • Part of an existing exclusion criterion was updated to be a stand-alone criterion (previously part of Exclusion 205, the following is now Exclusion 206: receiving systemic immunosuppressive therapy (> 2 weeks) within 7 days prior to the first dose of study treatment, including oral steroid doses > 10 mg/day of prednisone or equivalent except for management of adverse events during the course of the study. Subjects that require intermittent use of bronchodilators or local steroid injection will not be excluded from the study). • Updated exclusion criteria to include only highly effective methods of birth control which are in accordance with CTFG’s recommendations (removed statements regarding barrier methods of contraception as being acceptable). - Others

15 Jun 2018

 Updated Section 2.4 and Section 2.5 with Merck-provided language for pembrolizumab product background.  Updated Section 3.4 to clarify that all subjects who are not DLT evaluable can be replaced.  Updated Section 3.5.1 to clarify the data collected for subjects who continue past 12 months and up to 24 months on treatment.  Updated Section 4 to clarify that all windows in Inclusion and Exclusion criteria are relative to first day of study treatment.  Modified Exclusion Criterion to exclude subjects with history of or active pneumonitis.  Updated relevant sections to require safety labs to be reviewed within 2 days prior to dosing.  Updated Table 2 to indicate that pembrolizumab should be permanently discontinued for Recurrent Grade 2 pneumonitis.  Updated Table 2 with footnote to indicate that treatment may possibly continue under certain circumstances of isolated elevated AST attributed to AMG 820 with agreement from Medical Monitor.  Updated Table 3 to indicate that pembrolizumab should be permanently discontinued for Recurrent Grade 2 pneumonitis or ILD.  Provided language for corticosteroid treatment of Hepatic Toxicity (Section 6.2.4.6) or Renal Failure or Nephritis (Section 6.2.4.7): Grade 2 events should be treated with IV or oral corticosteroids while grade 3-4 events should be treated with IV corticosteroids.  Updated the reporting period of Pembrolizumab Events of Clinical Interest to be after the first dose of pembrolizumab through 135 (+7) days after the last dose of pembrolizumab, or 135 (+7) days after initiation of a new cancer therapy. - Updated Section 6.2.4.10 through Section 6.2.4.10.4 to include AMG 820 as well as pembrolizumab in diet and other considerations while taking treatment. - As Amgen has decided to discontinue investigating the combination of AMG 820 and pembrolizumab, removed non-essential biomarker and tissue sample collection from Schedule of Assessments. - others

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: A Phase 1b/2 Study Assessing Safety and Anti-tumor Activity of AMG 820 in Combination With Pembrolizumab in Select Advanced Solid Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Participants with Dose Limiting Toxicities (DLT)

Primary: Participants with Dose Limiting Toxicities (DLT)

Primary: Participants with Treatment -Emergent Adverse Events (TEAEs)

Primary: Participants with Treatment -Emergent Adverse Events (TEAEs)

Primary: Participants with Treatment -Emergent Adverse Events (TEAEs) Related to AMG 820 Treatment

Primary: Participants with Treatment -Emergent Adverse Events (TEAEs) Related to AMG 820 Treatment

Primary: Participants with Treatment -Emergent Adverse Events (TEAEs) Related to Pembrolizumab Treatment

Primary: Participants with Treatment -Emergent Adverse Events (TEAEs) Related to Pembrolizumab Treatment

Primary: Objective Response Rate (ORR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST)

Primary: Objective Response Rate (ORR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST)

Secondary: Time to Response (TTR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) For Participants Who Responded

Secondary: Time to Response (TTR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) For Participants Who Responded

Secondary: Time to Progression (TTP) for Participants Who had Progressive Disease

Secondary: Time to Progression (TTP) for Participants Who had Progressive Disease

Secondary: Kaplan-Meier Estimates for Overall Survival (OS) at Month 6 and Month 12

Secondary: Kaplan-Meier Estimates for Overall Survival (OS) at Month 6 and Month 12

Secondary: Kaplan-Meier Estimates for Progression-Free Survival (PFS) as per irRECIST at Month 6 and Month 12

Secondary: Kaplan-Meier Estimates for Progression-Free Survival (PFS) as per irRECIST at Month 6 and Month 12

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Time of Maximum Observed Concentration (tmax) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Time of Maximum Observed Concentration (tmax) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Maximum Observed Drug Concentration (Cmax) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Maximum Observed Drug Concentration (Cmax) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve last (AUClast) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve last (AUClast) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve Over the Dose Interval (AUCtau) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve Over the Dose Interval (AUCtau) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Minimum Observed Drug Concentration (Cmin) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Minimum Observed Drug Concentration (Cmin) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Terminal Elimination Half-life (t1/2z) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Terminal Elimination Half-life (t1/2z) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Volume of Distribution (Vz) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Volume of Distribution (Vz) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Drug Clearance (CL) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Drug Clearance (CL) During Treatment Cycles 1 + 2

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Accumulation Ratio (AR)

Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Accumulation Ratio (AR)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 1b/2 Study Assessing Safety and Anti-tumor Activity of AMG 820 in Combination With Pembrolizumab in Select Advanced Solid Tumors