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Clinical Trial Results:
A Phase 2/3 Trial to Evaluate Margetuximab in Combination with INCMGA00012 and Chemotherapy or MGD013 and Chemotherapy in Patients with Metastatic or Locally Advanced, Treatment-naïve, HER2-Positive Gastric or Gastroesophageal Junction Cancer

Summary
EudraCT number	2019-004699-21
Trial protocol	DE GB PL IT
Global end of trial date	25 Mar 2025

Results information
Results version number	v1(current)
This version publication date	13 Jun 2025
First version publication date	13 Jun 2025
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

CP-MGAH22-06

ISRCTN number

US NCT number

NCT04082364

WHO universal trial number (UTN)

Sponsor organisation name

MacroGenics, Inc

Sponsor organisation address

9704 Medical Center Drive, Rockville, MD, United States, 20850

Public contact

Global Trial Manager, MacroGenics, Inc., 301 2515172, info@macrogenics.com

Scientific contact

Global Trial Manager, MacroGenics, Inc., 301 2515172, info@macrogenics.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

Interim

Date of interim/final analysis

26 Sep 2024

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Jan 2024

Global end of trial reached?

Yes

Global end of trial date

25 Mar 2025

Was the trial ended prematurely?

Main objective of the trial

Cohort A: To evaluate the safety and tolerability of margetuximab + retifanlimab in patients with untreated locally advanced or metastatic gastric cancer (GC) or gastroesophageal junction (GEJ) cancer that is human epidermal growth factor 2 (HER2) immunohistochemistry (IHC) 3+ and PD-L1+ by IHC staining. To evaluate the ORR of margetuximab plus retifanlimab for non-MSI-H patients in the response evaluable population (REP) using Investigator-assessed radiology reviews. Cohort B, Part 1: To select the best margetuximab, chemotherapy and CPI-containing combination regimen for further evaluation in Part 2, based on evaluation of safety and ORR in the primary response evaluable population (PREP) of patients with GC or GEJ cancer, irrespective of PD-L1 status. Note: This objective was removed under Protocol Amendment 5.

Protection of trial subjects

This study was conducted under United States Investigational New Drug application, in compliance with Good Clinical Practice, as well as all applicable local and national laws and regulations of countries in which the trial was performed. At each trial site, an institutional review board (IRB) or independent ethics committee (IEC) reviewed and approved the clinical trial protocol, the current and previous versions of the Investigator’s Brochure, and informed consent form(s), as applicable. The IRB/IEC subsequently approved protocol amendments and revisions. Investigators were responsible for obtaining and documenting written informed consent from each participant or legal representative. Written informed consent was obtained for all participants before any protocol-specific procedures or interventions were performed.

Background therapy

Part A contained no background therapy Part B used a background chemotherapy combination of either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX-6), or capecitabine and oxaliplatin (XELOX),commonly used regimens for first-line HER2 positive GC and GEJ cancer patients worldwide. The investigator selected the background therapy.

Evidence for comparator

Actual start date of recruitment

30 Sep 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 2

Country: Number of subjects enrolled

United Kingdom: 1

Country: Number of subjects enrolled

Italy: 1

Country: Number of subjects enrolled

Korea, Republic of: 19

Country: Number of subjects enrolled

Singapore: 1

Country: Number of subjects enrolled

United States: 24

Country: Number of subjects enrolled

China: 29

Country: Number of subjects enrolled

Taiwan: 5

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

Screening details

Participants with untreated locally advanced unresectable or metastatic HER2+ gastric or gastroesophageal adenocarcinoma.

Period 1 title

Entire study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort B: Control Arm

Arm description

Arm type

Active comparator

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Herceptin

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

8 mg/kg loading dose, then 6 mg/kg, every 3 weeks

Investigational medicinal product name

Background chemotherapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

One of two background chemotherapy regimens could be selected by the investigator; 1) modified FOLFOX-6: fluorouracil IV bolus (400 mg/m2), fluorouracil IV infusion (2400 mg/m2 over 48 hours), leucovorin IV (400 mg/m2) and oxaliplatin IV (85 mg/m2) (mFOLFOX-6), every 2 weeks 2) XELOX: capecitabine 1000 mg/m2 orally twice daily for 14/21 days, and oxaliplatin IV (130 mg/m2, every 3 weeks)

Cohort B: Experimental Arm 1

Arm description

Arm type

Experimental

Investigational medicinal product name

Margetuximab

Investigational medicinal product code

Other name

MGAH22

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

15 mg/kg IV, every 3 weeks

Investigational medicinal product name

Background chemotherapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Retifanlimab

Investigational medicinal product code

Other name

INCMAG00012, MGA012

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

375 mg IV, every 3 weeks

Cohort B: Experimental Arm 2

Arm description

Arm type

Experimental

Investigational medicinal product name

Margetuximab

Investigational medicinal product code

Other name

MGAH22

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

15 mg/kg IV, every 3 weeks

Investigational medicinal product name

Tebotelimab

Investigational medicinal product code

Other name

MGD013

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

600 mg IV, every 3 weeks

Investigational medicinal product name

Background chemotherapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cohort B: Experimental Arm 3

Arm description

Arm type

Experimental

Investigational medicinal product name

Margetuximab

Investigational medicinal product code

Other name

MGAH22

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

15 mg/kg IV, every 3 weeks

Investigational medicinal product name

Background chemotherapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cohort A: Chemotherapy-free Arm

Arm description

Arm type

Experimental

Investigational medicinal product name

Margetuximab

Investigational medicinal product code

Other name

MGAH22

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

15 mg/kg IV, every 3 weeks

Investigational medicinal product name

Retifanlimab

Investigational medicinal product code

Other name

INCMAG00012, MGA012

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

375 mg IV, every 3 weeks

Number of subjects in period 1	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm
Started	8	10	6	10	48
Completed	2	7	3	2	17
Not completed	6	3	3	8	31
Physician decision	1	1	-	2	1
Consent withdrawn by subject	1	1	-	-	1
Death	1	1	1	2	23
Study terminated by sponsor	2	-	2	3	5
Lost to follow-up	1	-	-	-	1
Progression of disease	-	-	-	1	-

Baseline characteristics

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Reporting group title

Cohort B: Control Arm

Reporting group description

Reporting group title

Cohort B: Experimental Arm 1

Reporting group description

Reporting group title

Cohort B: Experimental Arm 2

Reporting group description

Reporting group title

Cohort B: Experimental Arm 3

Reporting group description

Reporting group title

Cohort A: Chemotherapy-free Arm

Reporting group description

Reporting group values	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm	Total
Number of subjects	8	10	6	10	48	82
Age categorical
Units: Subjects
Adults (18-64 years)	5	6	3	6	25	45
From 65-84 years	3	4	3	4	23	37
85 years and over	0	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	61.4 ( 7.25 )	61.8 ( 7.64 )	60.0 ( 16.45 )	60.5 ( 19.70 )	62.9 ( 12.25 )	-
Gender categorical
Units: Subjects
Female	1	2	4	1	6	14
Male	7	8	2	9	42	68

Subject analysis set title

Cohort A Response Evaluable Population

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All patients who received at least one dose of study treatment and had baseline radiographic tumor assessment. This population will be used for objective response related efficacy analyses.

Subject analysis set title

Cohort B: Response Evaluable Population

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All patients who were assigned to Cohort B, received at least one dose of study treatment, and had baseline radiographic tumor assessment. This population will be used for objective response related efficacy analyses

Subject analysis set title

ITT Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All patients who are assigned to treatment in Cohort A and all participants who are randomized into Cohort B of the study.

Subject analysis set title

Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All patients who receive at least one dose of study drug.

Subject analysis sets values	Cohort A Response Evaluable Population	Cohort B: Response Evaluable Population	ITT Population	Safety population
Number of subjects	48	33	82	81
Age categorical
Units: Subjects
Adults (18-64 years)	25	20	20	45
From 65-84 years	23	13	14	36
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	62.9 ( 12.25 )	( )	62.5 ( 10.30 )	( )
Gender categorical
Units: Subjects
Female	6	8	14	14
Male	42	25	68	67

End points

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Reporting group title

Cohort B: Control Arm

Reporting group description

Reporting group title

Cohort B: Experimental Arm 1

Reporting group description

Reporting group title

Cohort B: Experimental Arm 2

Reporting group description

Reporting group title

Cohort B: Experimental Arm 3

Reporting group description

Reporting group title

Cohort A: Chemotherapy-free Arm

Reporting group description

Subject analysis set title

Cohort A Response Evaluable Population

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All patients who received at least one dose of study treatment and had baseline radiographic tumor assessment. This population will be used for objective response related efficacy analyses.

Subject analysis set title

Cohort B: Response Evaluable Population

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

ITT Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All patients who are assigned to treatment in Cohort A and all participants who are randomized into Cohort B of the study.

Subject analysis set title

Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All patients who receive at least one dose of study drug.

Primary: Type and number of adverse events in Cohort A

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End point title

Type and number of adverse events in Cohort A ^[1]

End point description

End point type

Primary

End point timeframe

Adverse events are recorded from the time of informed consent signature through 30 days of the last dose of study treatment

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: Data displays were summary tables with the number and percent of participants who experienced a given event. There is no active control or comparator to allow for statistical inferences.

End point values	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm	Safety population
Number of subjects analysed	0 ^[2]	0 ^[3]	0 ^[4]	0 ^[5]	48	81
Units: participants
Study treatment related adverse event					38	38
Severe adverse event					25	25
Severe study treatment-related adverse event					12	12
Study treatment-related serious adverse event					9	9
Fatal adverse event					2	2
Number not assigned to Part A					0	33

Notes
[2] - This is not an end point for Cohort B of the study.
[3] - This is not an end point for Cohort B of the study.
[4] - This is not an end point for Cohort B of the study.
[5] - This is not an end point for Cohort B of the study.

No statistical analyses for this end point

Primary: Objective response rate in Cohort A

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End point title

Objective response rate in Cohort A ^[6]

End point description

The percentage of patients who have a complete or partial response to study treatment.

End point type

Primary

End point timeframe

From the first dose of study treatment throughout the study

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analysis is not indicated for single-arm evaluation of Objective Response Rate.

End point values	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm	Cohort A Response Evaluable Population
Number of subjects analysed	0 ^[7]	0 ^[8]	0 ^[9]	0 ^[10]	48	48
Units: percentage
number (confidence interval 95%)	( to )	( to )	( to )	( to )	52.1 (37.2 to 66.7)	52.1 (37.2 to 66.7)

Notes
[7] - This is not an end point for Cohort B of the study.
[8] - This is not an end point for Cohort B of the study.
[9] - This is not an end point for Cohort B of the study.
[10] - This is not an end point for Cohort B of the study.

No statistical analyses for this end point

Secondary: Median duration of Response in Cohort A

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End point title

Median duration of Response in Cohort A

End point description

End point type

Secondary

End point timeframe

From the first date of complete or partial response to the date of first documented disease progression or death, whichever is first.

End point values	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm	Cohort A Response Evaluable Population
Number of subjects analysed	0 ^[11]	0 ^[12]	0 ^[13]	0 ^[14]	25 ^[15]	25 ^[16]
Units: Months
median (confidence interval 95%)	( to )	( to )	( to )	( to )	16.1 (9.00 to 21.91)	16.1 (9.00 to 21.91)

Notes
[11] - This is not an end point for Cohort B of the study.
[12] - This is not an end point for Cohort B of the study.
[13] - This is not an end point for Cohort B of the study.
[14] - This is not an end point for Cohort B of the study.
[15] - Only 25/48 participants responded to treatment and were assessed for duration of response.
[16] - Only 25/48 participants responded to treatment and were assessed for duration of response.

No statistical analyses for this end point

Secondary: Median progression-free survival in Cohort A

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End point title

Median progression-free survival in Cohort A

End point description

End point type

Secondary

End point timeframe

Progression-free survival is assessed from the first dose of study treatment until documented disease progression or death, whichever comes first.

End point values	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm	Cohort A Response Evaluable Population
Number of subjects analysed	0 ^[17]	0 ^[18]	0 ^[19]	0 ^[20]	48	48
Units: Months
median (confidence interval 95%)	( to )	( to )	( to )	( to )	9.8 (4.60 to 14.75)	9.8 (4.60 to 14.75)

Notes
[17] - This is not an end point for Cohort B of the study.
[18] - This is not an end point for Cohort B of the study.
[19] - This is not an end point for Cohort B of the study.
[20] - This is not an end point for Cohort B of the study.

No statistical analyses for this end point

Secondary: Objective response rate in Cohort B

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End point title

Objective response rate in Cohort B

End point description

End point type

Secondary

End point timeframe

From the first dose of study treatment throughout the study

End point values	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm	Cohort B: Response Evaluable Population
Number of subjects analysed	8	9	6	10	0 ^[21]	33
Units: percentage
number (confidence interval 95%)	62.5 (24.5 to 91.5)	88.9 (51.8 to 99.7)	83.3 (35.9 to 99.6)	90.0 (55.5 to 99.7)	( to )	81.8 (64.5 to 93.0)

Notes
[21] - This is not an end point for Cohort A of the study.

No statistical analyses for this end point

Secondary: Number of participants who develop anti-drug antibodies to margetuximab

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End point title

Number of participants who develop anti-drug antibodies to margetuximab

End point description

End point type

Secondary

End point timeframe

From the first dose of study treatment throughout the study treatment.

End point values	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm	Safety population
Number of subjects analysed	0 ^[22]	9	6	10	48	81
Units: participants
Negative at baseline, negative post-baseline		8	5	10	40	63
Negative at baseline, positive post-baseline		1	0	0	5	6
Positive at baseline, negative post-baseline		0	0	0	2	2
not done at baseline, negative post-baseline		0	1	0	1	2
Did not receive margetuximab		0	0	0	0	8

Notes
[22] - Participants in this arm did not receive margetuximab.

No statistical analyses for this end point

Secondary: Number of participants who develop anti-drug antibodies to retifanlimab

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End point title

Number of participants who develop anti-drug antibodies to retifanlimab

End point description

End point type

Secondary

End point timeframe

From the first dose of study treatment throughout study treatment.

End point values	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm	Safety population
Number of subjects analysed	0 ^[23]	9	0 ^[24]	0 ^[25]	48	81
Units: participants
Negative at baseline, negative post-baseline		9			43	52
Negative at baseline, positive post -baseline		0			3	3
Positive at baseline, negative post baseline		0			1	1
Not done at baseline, negative post baseline		0			1	1
Did not receive retifanlimab		0			0	24

Notes
[23] - This arm did not receive retifanlimab, and is not evaluable for retifanlimab ADA.
[24] - This arm did not receive retifanlimab, and is not evaluable for retifanlimab ADA.
[25] - This arm did not receive retifanlimab, and is not evaluable for retifanlimab ADA.

No statistical analyses for this end point

Secondary: Number of participants who develop anti-drug antibodies to tebotelimab

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End point title

Number of participants who develop anti-drug antibodies to tebotelimab

End point description

End point type

Secondary

End point timeframe

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End point values	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm	Safety population
Number of subjects analysed	0 ^[26]	0 ^[27]	6	0 ^[28]	0 ^[29]	81
Units: participants
Negative at baseline, negative post-baseline			1			1
Negative at baseline, positive post-baseline			4			4
Negative at baseline, not done post-baseline			1			1
Did not receive tebotelimab			0			75

Notes
[26] - This treatment group did not receive tebotelimab
[27] - This treatment group did not receive tebotelimab
[28] - This treatment group did not receive tebotelimab
[29] - This treatment group did not receive tebotelimab

No statistical analyses for this end point

Secondary: Disease control rate

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End point title

Disease control rate

End point description

End point type

Secondary

End point timeframe

Disease control rate is measured from the randomization until 3 months after the first dose of study treatment for each participant.

End point values	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm	Cohort A Response Evaluable Population	Cohort B: Response Evaluable Population
Number of subjects analysed	8	9	6	10	48	48	33
Units: percentage
number (confidence interval 95%)	87.5 (47.3 to 99.7)	100.0 (66.4 to 100.0)	100.0 (54.1 to 100.0)	100.0 (69.2 to 100.0)	83.3 (69.8 to 92.5)	83.3 (69.8 to 92.5)	97.0 (84.2 to 99.9)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs were collected from the time of the first dose through 30 days after the last dose, average 6 month. All-cause mortality was collected from the first dose throughout the follow up period.

Adverse event reporting additional description

AEs are based on physical exam, participant reports, and significant abnormal laboratory values. AEs were not collected in survival follow up. Only SAEs were collected in survival follow- if related to study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Cohort B: Control Arm

Reporting group description

Reporting group title

Cohort B: Experimental Arm 1

Reporting group description

Reporting group title

Cohort B: Experimental Arm 2

Reporting group description

Reporting group title

Cohort B: Experimental Arm 3

Reporting group description

Reporting group title

Cohort A: Chemotherapy-free Arm

Reporting group description

Serious adverse events	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 8 (25.00%)	4 / 9 (44.44%)	5 / 6 (83.33%)	4 / 10 (40.00%)	20 / 48 (41.67%)
number of deaths (all causes)	1	1	1	2	25
number of deaths resulting from adverse events				1
Investigations
Platelet count decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant ovarian cyst
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest discomfort
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Dysphagia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	2 / 48 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
oesophageal ulcer
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumatosis intestinalis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary obstruction
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Combined pulmonary fibrosis and emphysema
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune-mediated lung disease
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	2 / 48 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash maculo-papular
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Immune-mediated renal disorder
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary incontinence
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Thyroiditis subacute
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
bacterial sepsis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza A
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Metabolism and nutrition disorders
Diabetic ketoacidosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	2 / 48 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort B: Control Arm	Cohort B: Experimental Arm 1	Cohort B: Experimental Arm 2	Cohort B: Experimental Arm 3	Cohort A: Chemotherapy-free Arm
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 8 (87.50%)	9 / 9 (100.00%)	6 / 6 (100.00%)	10 / 10 (100.00%)	47 / 48 (97.92%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	6 / 48 (12.50%)
occurrences all number	0	0	0	0	6
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	2 / 10 (20.00%)	3 / 48 (6.25%)
occurrences all number	0	0	1	2	4
Fatigue
subjects affected / exposed	1 / 8 (12.50%)	2 / 9 (22.22%)	1 / 6 (16.67%)	0 / 10 (0.00%)	14 / 48 (29.17%)
occurrences all number	2	2	2	0	22
Oedema peripheral
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	9 / 48 (18.75%)
occurrences all number	2	0	0	1	19
Pyrexia
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 6 (16.67%)	2 / 10 (20.00%)	9 / 48 (18.75%)
occurrences all number	1	0	4	4	12
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 8 (12.50%)	3 / 9 (33.33%)	0 / 6 (0.00%)	0 / 10 (0.00%)	7 / 48 (14.58%)
occurrences all number	1	4	0	0	9
Dyspnoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	9 / 48 (18.75%)
occurrences all number	0	0	0	0	14
Psychiatric disorders
Anxiety disorder
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	5 / 48 (10.42%)
occurrences all number	0	0	0	0	7
Insomnia
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	1 / 6 (16.67%)	0 / 10 (0.00%)	7 / 48 (14.58%)
occurrences all number	1	1	2	0	7
Investigations
Alanine aminotransferase increased
subjects affected / exposed	3 / 8 (37.50%)	5 / 9 (55.56%)	0 / 6 (0.00%)	5 / 10 (50.00%)	2 / 48 (4.17%)
occurrences all number	3	6	0	17	2
Aspartate aminotransferase increased
subjects affected / exposed	4 / 8 (50.00%)	6 / 9 (66.67%)	3 / 6 (50.00%)	3 / 10 (30.00%)	2 / 48 (4.17%)
occurrences all number	6	10	6	13	3
Blood bilirubin increased
subjects affected / exposed	3 / 8 (37.50%)	2 / 9 (22.22%)	1 / 6 (16.67%)	4 / 10 (40.00%)	0 / 48 (0.00%)
occurrences all number	5	2	2	12	0
Blood creatine increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	5 / 48 (10.42%)
occurrences all number	0	0	0	0	12
Ejection fraction decreased
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 10 (20.00%)	3 / 48 (6.25%)
occurrences all number	1	0	0	2	4
Gamma-glutamyltransferase increased
subjects affected / exposed	3 / 8 (37.50%)	0 / 9 (0.00%)	2 / 6 (33.33%)	2 / 10 (20.00%)	0 / 48 (0.00%)
occurrences all number	5	0	2	2	0
Lymphocyte count decreased
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 6 (16.67%)	3 / 10 (30.00%)	1 / 48 (2.08%)
occurrences all number	5	0	4	8	1
Platelet count decreased
subjects affected / exposed	7 / 8 (87.50%)	7 / 9 (77.78%)	6 / 6 (100.00%)	7 / 10 (70.00%)	3 / 48 (6.25%)
occurrences all number	18	21	10	19	3
Weight decreased
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	3 / 6 (50.00%)	1 / 10 (10.00%)	9 / 48 (18.75%)
occurrences all number	1	1	6	1	12
White blood cell count decreased
subjects affected / exposed	4 / 8 (50.00%)	7 / 9 (77.78%)	4 / 6 (66.67%)	8 / 10 (80.00%)	1 / 48 (2.08%)
occurrences all number	12	22	9	15	1
Neutrophil count decreased
subjects affected / exposed	5 / 8 (62.50%)	7 / 9 (77.78%)	6 / 6 (100.00%)	10 / 10 (100.00%)	1 / 48 (2.08%)
occurrences all number	21	27	16	28	1
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	1 / 8 (12.50%)	3 / 9 (33.33%)	2 / 6 (33.33%)	4 / 10 (40.00%)	12 / 48 (25.00%)
occurrences all number	1	6	4	5	16
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	1 / 6 (16.67%)	0 / 10 (0.00%)	6 / 48 (12.50%)
occurrences all number	0	3	1	0	7
Headache
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	6 / 48 (12.50%)
occurrences all number	0	0	0	0	6
Neurotoxicity
subjects affected / exposed	1 / 8 (12.50%)	3 / 9 (33.33%)	1 / 6 (16.67%)	4 / 10 (40.00%)	0 / 48 (0.00%)
occurrences all number	1	3	1	4	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 8 (25.00%)	3 / 9 (33.33%)	5 / 6 (83.33%)	9 / 10 (90.00%)	14 / 48 (29.17%)
occurrences all number	9	6	8	28	23
Leukopenia
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	2 / 6 (33.33%)	3 / 10 (30.00%)	0 / 48 (0.00%)
occurrences all number	9	1	4	16	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	10 / 48 (20.83%)
occurrences all number	1	0	0	0	12
Constipation
subjects affected / exposed	2 / 8 (25.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	0 / 10 (0.00%)	8 / 48 (16.67%)
occurrences all number	2	2	0	0	8
Diarrhoea
subjects affected / exposed	2 / 8 (25.00%)	4 / 9 (44.44%)	2 / 6 (33.33%)	4 / 10 (40.00%)	18 / 48 (37.50%)
occurrences all number	2	8	5	8	26
Dyspepsia
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 10 (0.00%)	7 / 48 (14.58%)
occurrences all number	0	4	0	0	9
Nausea
subjects affected / exposed	2 / 8 (25.00%)	4 / 9 (44.44%)	1 / 6 (16.67%)	3 / 10 (30.00%)	16 / 48 (33.33%)
occurrences all number	3	10	1	7	24
Vomiting
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	2 / 6 (33.33%)	3 / 10 (30.00%)	16 / 48 (33.33%)
occurrences all number	1	3	2	9	23
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	1 / 8 (12.50%)	2 / 9 (22.22%)	1 / 6 (16.67%)	0 / 10 (0.00%)	10 / 48 (20.83%)
occurrences all number	1	3	1	0	16
Rash
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 10 (10.00%)	9 / 48 (18.75%)
occurrences all number	2	1	0	1	10
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 8 (12.50%)	2 / 9 (22.22%)	3 / 6 (50.00%)	0 / 10 (0.00%)	5 / 48 (10.42%)
occurrences all number	1	2	3	0	6
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	7 / 48 (14.58%)
occurrences all number	0	0	0	0	9
Back pain
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	0 / 10 (0.00%)	5 / 48 (10.42%)
occurrences all number	0	2	0	0	7
Infections and infestations
COVID-19
subjects affected / exposed	2 / 8 (25.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 10 (10.00%)	4 / 48 (8.33%)
occurrences all number	3	1	0	1	4
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 8 (25.00%)	3 / 9 (33.33%)	2 / 6 (33.33%)	1 / 10 (10.00%)	13 / 48 (27.08%)
occurrences all number	4	4	2	1	16
Hypoalbuminaemia
subjects affected / exposed	1 / 8 (12.50%)	2 / 9 (22.22%)	4 / 6 (66.67%)	6 / 10 (60.00%)	3 / 48 (6.25%)
occurrences all number	3	7	5	12	4
Hypocalcaemia
subjects affected / exposed	2 / 8 (25.00%)	1 / 9 (11.11%)	2 / 6 (33.33%)	2 / 10 (20.00%)	2 / 48 (4.17%)
occurrences all number	6	1	6	5	3
Hypokalaemia
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	2 / 6 (33.33%)	3 / 10 (30.00%)	8 / 48 (16.67%)
occurrences all number	1	1	2	10	8
Hyponatraemia
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	3 / 6 (50.00%)	2 / 10 (20.00%)	4 / 48 (8.33%)
occurrences all number	0	3	10	2	5

More information

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Were there any global substantial amendments to the protocol? Yes

06 Jun 2019

The criterion for defining uncontrolled hypertension in exclusion criterion 10(d) was reduced.

09 Aug 2019

The choice of backbone chemotherapy regimens was revised based on recommendation of the study steering committee Changes were made to the secondary objectives for Cohort B. The population of interest HER2+ /PD-1+ was more narrowly defined as also being non-MSI-high. Specific assays were specified for determining HER2 status Clarification to entry criterion 7: neoadjuvant and adjuvant immunotherapy is excluded. Cautionary statement related to the use of capecitabine or fluorouracil in combination with anticoagulants, phenytoin and CYP2C9 substrates was added. Cautionary statement related to the use of oxaliplatin and other potentially nephrotoxic compounds was added. Clarified that no pharmacokinetic or immunogenicity samples will be collect from participants in the control arm. Additional timepoints for collecting prothrombin time and international normalized ratio text were added.

26 Jan 2021

Cohort A was revised. MSI-high status is no longer required for study entry and the sample size was increased to 110. Fertility and contraception language was updated to be consistent with Clinical Trial Facilitation Group recommendations on contraception. Minor changes to the entry criteria were made for clarity. Stratification factors were revised from tumor location (stomach vs gastrointestinal junction) to HER2 testing (ICH2=/FISH+ vs ICH3+) The guidelines for premedication and prophylaxis was modified to allow substitution of equivalent medications based on local medical practice and availability. A typographical correction was made to correct 337 overall survival (OS ) events in Cohort B to 377 OS events. Updated the number of sites and countries participating in the study. Updated clinical experience information for margetuximab + pembrolizumab, tebotelimab (MGD013), and shorter infusion durations for margetuximab. Clarified that the ORR in Cohort A will be based on independent radiology review. Added that interruption of all components of chemotherapy for toxicity is limited to 2 consecutive cycles (6 weeks).

06 Jun 2022

The study halted enrollment due to a business decision and not a safety concern. Many changes were made to the protocol study design and procedures to support a timely closeout of the study. The requirement for independent assessment of response to treatment in Cohort A was removed. Final analysis will be conducted on investigator-assessed response. No sensitivity analysis will be conducted. In Cohort A: Secondary objective related to efficacy and Fcγ receptor was removed. Secondary objective related to PK and exposure-response analysis was removed. In Cohort B, Part 1: Primary objective removed because enrollment was closed at 33 patients. Selection of the best treatment arm will not be made. Secondary objectives related to efficacy were hanged to ORR and DCR only for each treatment arm. Secondary objectives related efficacy in the double positive and MSI-high subgroups were removed. Secondary objective related to efficacy and Fcγ receptor was removed. Secondary objective related to PK and exposure-response analysis was removed. Cohort B, Part 2: Primary and secondary objectives were removed because no patients were enrolled. General guidance for dose reductions for chemotherapy agents were added. A clarification was made to the language on when to restart chemotherapy-related toxicity. The definition of the end of the study was changed to after the last patient completes the safety follow-up period. Patients in survival follow-up will be discontinued from the study. Revised the analysis to descriptive PK summaries. PPK, exposure-response modeling, and influence of intrinsic and extrinsic covariates will not be performed. Language to indicate that collection of PK, PD and ADA samples is no longer required was added. Removed the analysis of patient reported outcomes, as no questionnaires were completed.

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 2/3 Trial to Evaluate Margetuximab in Combination with INCMGA00012 and Chemotherapy or MGD013 and Chemotherapy in Patients with Metastatic or Locally Advanced, Treatment-naïve, HER2-Positive Gastric or Gastroesophageal Junction Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Type and number of adverse events in Cohort A

Primary: Type and number of adverse events in Cohort A

Primary: Objective response rate in Cohort A

Primary: Objective response rate in Cohort A

Secondary: Median duration of Response in Cohort A

Secondary: Median duration of Response in Cohort A

Secondary: Median progression-free survival in Cohort A

Secondary: Median progression-free survival in Cohort A

Secondary: Objective response rate in Cohort B

Secondary: Objective response rate in Cohort B

Secondary: Number of participants who develop anti-drug antibodies to margetuximab

Secondary: Number of participants who develop anti-drug antibodies to margetuximab

Secondary: Number of participants who develop anti-drug antibodies to retifanlimab

Secondary: Number of participants who develop anti-drug antibodies to retifanlimab

Secondary: Number of participants who develop anti-drug antibodies to tebotelimab

Secondary: Number of participants who develop anti-drug antibodies to tebotelimab

Secondary: Disease control rate

Secondary: Disease control rate

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Phase 2/3 Trial to Evaluate Margetuximab in Combination with INCMGA00012 and Chemotherapy or MGD013 and Chemotherapy in Patients with Metastatic or Locally Advanced, Treatment-naïve, HER2-Positive Gastric or Gastroesophageal Junction Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Type and number of adverse events in Cohort A

Primary: Type and number of adverse events in Cohort A

Primary: Objective response rate in Cohort A

Primary: Objective response rate in Cohort A

Secondary: Median duration of Response in Cohort A

Secondary: Median duration of Response in Cohort A

Secondary: Median progression-free survival in Cohort A

Secondary: Median progression-free survival in Cohort A

Secondary: Objective response rate in Cohort B

Secondary: Objective response rate in Cohort B

Secondary: Number of participants who develop anti-drug antibodies to margetuximab

Secondary: Number of participants who develop anti-drug antibodies to margetuximab

Secondary: Number of participants who develop anti-drug antibodies to retifanlimab

Secondary: Number of participants who develop anti-drug antibodies to retifanlimab

Secondary: Number of participants who develop anti-drug antibodies to tebotelimab

Secondary: Number of participants who develop anti-drug antibodies to tebotelimab

Secondary: Disease control rate

Secondary: Disease control rate

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2/3 Trial to Evaluate Margetuximab in Combination with INCMGA00012 and Chemotherapy or MGD013 and Chemotherapy in Patients with Metastatic or Locally Advanced, Treatment-naïve, HER2-Positive Gastric or Gastroesophageal Junction Cancer