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Clinical Trial Results:
A Randomized Phase II Multicenter, Open-label Study Evaluating the Efficacy and Safety of IMAB362 in Combination with the EOX (Epirubicin, Oxaliplatin, Capecitabine) Regimen as First-line Treatment of Patients with CLDN18.2-positive Advanced Adenocarcinomas of the Stomach, the Esophagus or the Gastroesophageal Junction (FAST)

Summary
EudraCT number	2011-005285-38
Trial protocol	DE CZ LV BG
Global end of trial date	31 Jan 2019

Results information
Results version number	v1(current)
This version publication date	04 Jan 2020
First version publication date	04 Jan 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

GM-IMAB-001-03

ISRCTN number

US NCT number

NCT01630083

WHO universal trial number (UTN)

Other trial identifiers

Acronym: FAST, Other study number: 8951-CL-0202

Sponsor organisation name

Astellas Pharma Global Development, Inc.

Sponsor organisation address

1 Astellas Way, Northbrook, IL, United States, 60062

Public contact

Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., astellas.resultsdisclosure@astellas.com

Scientific contact

Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., astellas.resultsdisclosure@astellas.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

31 Jan 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

31 Jan 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to evaluate the efficacy of zolbetuximab in combination with EOX as determined by progression-free survival (PFS) and to determine the safety and tolerability of zolbetuximab in combination with EOX.

Protection of trial subjects

This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Jul 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

12 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 18

Country: Number of subjects enrolled

Czech Republic: 4

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

Latvia: 25

Country: Number of subjects enrolled

Russian Federation: 105

Country: Number of subjects enrolled

Ukraine: 77

Worldwide total number of subjects

252

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)

199

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Male & female participants with CLDN18.2-positive advanced adenocarcinomas of the stomach, esophagus or gastroesophageal junction were enrolled in this multinational, multicenter study. Participants who had a tumor with 2+ or 3+ CLDN18.2 staining intensity in at least 40% of the tumor cells based on immunohistochemical testing were eligible.

Screening details

Participants were randomized in two arms in a 1:1 ratio which was later adjusted to 1:1:7 to allow recruitment in Arm 3 which was added at a later date, to catch up with arms 1 & 2. Randomization was later adjusted to 1:1:1 and stratified by CLDN18.2 positivity and presence of nonmeasurable vs measurable disease at baseline.

Number of subjects started

730 ^[1]

Intermediate milestone: Number of subjects

Screen failed: 478

Number of subjects completed

252

Reason: Number of subjects

Claudin-18 splice variant 2 (CLDN18.2) negative: 352

Reason: Number of subjects

CLDN18.2 positive but other criteria not fulfilled: 82

Reason: Number of subjects

CLDN18.2 not assessable: 44

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The worldwide number includes all randomized participants, the pre-assignment period includes participants in the screening period.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

EOX Treatment

Arm description

Participants received up to 8 cycles of epirubicin, oxaliplatin and capecitabine (EOX) chemotherapy treatment alone (50 mg/m^2 epirubicin intravenously on day 1 of each cycle, 130 mg/m^2 oxaliplatin intravenously on day 1 of each cycle, 625 mg/m^2 capecitabine orally twice daily on days 1 to 21 of each cycle). The first dose of capecitabine taken in the evening of day 1.

Arm type

Experimental

Investigational medicinal product name

epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Epirubicin was administered at a dose of 50 mg/m^2 as a 15-minute intravenous infusion on day 1 of each cycle.

Investigational medicinal product name

capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The daily dose of capecitabine was 1250 mg/m^2. Capecitabine tablets were given once daily at a dose of 625 mg/m^2 orally in the evening of day 1 of each cycle and twice daily at a dose of 625 mg/m^2 orally on days 2 to 21 of each cycle; the morning dose of capecitabine on day 1 of each cycle was omitted due to administration of zolbetuximab, epirubicin and oxaliplatin.

Investigational medicinal product name

oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin was administered at a dose of 130 mg/m^2 as a 2-hour intravenous infusion on day 1 of each cycle.

EOX+zolbetuximab 800/600 mg/m^2

Arm description

Participants received up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab administered as loading dose of 800 mg/m^2 intravenously on day 1 of cycle 1 followed by 600 mg/m^2 intravenously on day 1 of each subsequent cycle. Zolbetuximab was administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants were permitted to continue zolbetuximab monotherapy (600 mg/m^2 every 3 weeks administered intravenously as a 2-hour infusion) until progressive disease (PD), withdrawal of consent or unacceptable toxicity. PD per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study, an absolute increase of at least 5mm must also be demonstrated, unequivocal progression of existing non-target lesions and appearance of one or more new lesions was considered progression.

Arm type

Experimental

Investigational medicinal product name

epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Epirubicin was administered at a dose of 50 mg/m^2 as a 15-minute intravenous infusion on day 1 of each cycle.

Investigational medicinal product name

capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

zolbetuximab

Investigational medicinal product code

IMAB362

Other name

Pharmaceutical forms

Powder and solvent for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Two different formats of zolbetuximab, comprising different strengths, were provided. Vials contained 22 mg or 105 mg of zolbetuximab. Prior to administration, zolbetuximab was reconstituted with 1.1 mL (22 mg zolbetuximab vials) or 5.0 mL (105 mg zolbetuximab vials) water for injection, which resulted in a concentration of 20 mg/mL zolbetuximab. The extractable volume per vial was 1 mL (for 22 mg zolbetuximab vials) or 5 mL (for 105 mg zolbetuximab vials). The reconstituted solution was further diluted with sodium chloride 0.9% to a final concentration of 2 mg/mL zolbetuximab. Zolbetuximab was administered as an intravenous infusion over 2 to 3 hours.

Investigational medicinal product name

oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin was administered at a dose of 130 mg/m^2 as a 2-hour intravenous infusion on day 1 of each cycle.

EOX+zolbetuximab 1000 mg/m^2

Arm description

Participants received up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab 1000 mg/m^2 intravenously on day 1 of each cycle. Zolbetuximab was administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants were permitted to continue zolbetuximab monotherapy (1000 mg/m^2 every 3 weeks administered intravenously as a 2-hour infusion ) until PD, withdrawal of consent or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Epirubicin was administered at a dose of 50 mg/m^2 as a 15-minute intravenous infusion on day 1 of each cycle.

Investigational medicinal product name

zolbetuximab

Investigational medicinal product code

IMAB362

Other name

Pharmaceutical forms

Powder and solvent for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin was administered at a dose of 130 mg/m^2 as a 2-hour intravenous infusion on day 1 of each cycle.

Number of subjects in period 1	EOX Treatment	EOX+zolbetuximab 800/600 mg/m^2	EOX+zolbetuximab 1000 mg/m^2
Started	85	79	88
Treated	84	77	85
Discontinued within 8 cycles	52	42	45
Continued zolbetuximab monotherapy	0 ^[2]	32 ^[3]	27 ^[4]
Completed	32	34	38
Not completed	53	45	50
Clinical progression	8	1	2
Adverse event (AE)/Serious Adverse Event (SAE)	3	4	3
EOX not completed cont. zolbetuximab	-	1	2
Randomized but not treated	1	2	3
Significant protocol violation	2	-	1
Miscellaneous	4	4	1
Withdrawal of consent	8	10	11
Confirmed progression per RECIST v1.1	21	19	21
Lost to follow-up	-	1	-
Change in patient’s condition	6	3	6

Notes
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: No participants in Arm 1 continued on to receive zolbetuximab as a single-agent maintenance treatment after the EOX phase.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: A total of 32 participants in Arm 2 continued to receive zolbetuximab as a single-agent maintenance treatment after the EOX phase.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: A total of 27 participants in Arm 3 continued to receive zolbetuximab as a single-agent maintenance treatment after the EOX phase.

Baseline characteristics

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Reporting group title

EOX Treatment

Reporting group description

Reporting group title

EOX+zolbetuximab 800/600 mg/m^2

Reporting group description

Reporting group title

EOX+zolbetuximab 1000 mg/m^2

Reporting group description

Reporting group values	EOX Treatment	EOX+zolbetuximab 800/600 mg/m^2	EOX+zolbetuximab 1000 mg/m^2	Total
Number of subjects	85	79	88
Age categorical
Units: Subjects
Age continuous
The baseline characteristics consisted of the all randomized population.
Units: years
arithmetic mean (standard deviation)	55.9 ± 10.5	56.8 ± 11.8	57.4 ± 9.8	-
Gender categorical
Units: Subjects
M	57	48	59	164
F	28	31	29	88
Location of Tumor at First Diagnosis
Units: Subjects
ESOPHAGUS	4	2	0	6
GASTROESOPHAGEAL JUNCTION	12	14	8	34
STOMACH	69	63	80	212
Measurable Disease
Units: Subjects
MEASURABLE	67	66	61	194
NON-MEASURABLE	18	13	27	58
Race
Units: Subjects
WHITE	81	75	86	242
OTHER	4	4	2	10
Result of CLDN18.2 IHC Test
Units: Subjects
2+	35	26	43	104
3+	50	53	45	148
Time since First Diagnosis (months)
Units: Year
arithmetic mean (standard deviation)	4.3 ± 6.4	8.2 ± 16.3	6.4 ± 11.8	-

End points

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Reporting group title

EOX Treatment

Reporting group description

Reporting group title

EOX+zolbetuximab 800/600 mg/m^2

Reporting group description

Reporting group title

EOX+zolbetuximab 1000 mg/m^2

Reporting group description

Primary: Progression-free Survival (PFS)

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End point title

Progression-free Survival (PFS)

End point description

PFS was defined as the time from randomization to the first observation of disease progression (based on central reading) or death from any cause (as assessed by the independent reviewer). Participants without documented progression or death were censored as of the last tumor evaluation determining lack of progression. The analysis population consisted of the full analysis set (FAS) which consisted of all participants who were randomized and received at least 1 dose of any study medication.

End point type

Primary

End point timeframe

From randomization to the data cut-off date of 31JAN2019; maximum time on follow-up was, 68.2, 47.2 & 59.6 months in the EOX, EOX+Zolbetuximab 600 mg, and EOX+Zolbetuximab 1000 mg treatment groups respectively.

End point values	EOX Treatment	EOX+zolbetuximab 800/600 mg/m^2	EOX+zolbetuximab 1000 mg/m^2
Number of subjects analysed	84	77	85
Units: months
median (confidence interval 95%)	5.3 (4.1 to 7.1)	7.5 (5.6 to 11.3)	7.1 (5.6 to 8.0)

PFS Treatment Comparison (Arm 1 versus Arm 2)

Comparison groups

EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.0005 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.44

Confidence interval

level

95%

sides

2-sided

lower limit

0.29

upper limit

0.67

Notes
[1] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[2] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.

PFS Treatment Comparison (Arm 1 versus Arm 3)

Comparison groups

EOX Treatment v EOX+zolbetuximab 1000 mg/m^2

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.0114 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.58

Confidence interval

level

95%

sides

2-sided

lower limit

0.39

upper limit

0.85

Notes
[3] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[4] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.

PFS Treatment Comparison (Arm 3 versus Arm 2)

Comparison groups

EOX+zolbetuximab 800/600 mg/m^2 v EOX+zolbetuximab 1000 mg/m^2

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.2842 ^[6]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

1.18

Notes
[5] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[6] - The analyses were performed using a 2-sided test at the 5% significance level for the comparison of Arm 3 vs Arm 2.

Primary: Number of Participants with Adverse Events (AEs)

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End point title

Number of Participants with Adverse Events (AEs) ^[7]

End point description

An AE was defined as any unintended or undesirable, noxious or pathological change, compared to pre-existing conditions, experienced by a participant during a clinical study or the follow-up period, regardless of relationship to study medication. Treatment-emergent adverse event (TEAE) were those AEs that started or worsened after the first dose of study medication. The analysis population consisted of the safety analysis set (SAF) which consisted of all participants who received at least 1 dose of any study medication.

End point type

Primary

End point timeframe

From the first dose of study drug administration up to 30 days after the last study medication administration (up to 1791 days).

Notes
[7] - 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 analyses not applicable, only descriptive statistics data applicable for this endpoint.

End point values	EOX Treatment	EOX+zolbetuximab 800/600 mg/m^2	EOX+zolbetuximab 1000 mg/m^2
Number of subjects analysed	84	77	85
Units: participants
Any TEAE	84	74	85
Grade ≥ 3 TEAEs	54	54	58
Serious TEAEs	27	19	17
Study drug-related TEAEs	80	74	83
Study drug-related TEAEs - zolbetuximab	0	64	73
Study drug-related TEAEs - epirubicin	76	70	77
Study drug-related TEAEs - oxaliplatin	76	71	74
Study drug-related TEAEs - capecitabine	78	70	75
Study drug-related serious TEAEs	5	8	5
Study drug-related serious TEAEs - zolbetuximab	0	1	0
Study drug-related serious TEAEs - epirubicin	4	6	3
Study drug-related serious TEAEs - oxaliplatin	4	7	3
Study drug-related serious TEAEs - capecitabine	5	8	5
TEAEs leading to withdrawal of zolbetuximab	0	10	11
Fatal TEAEs	15	8	9

No statistical analyses for this end point

Secondary: Clinical PFS

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End point title

Clinical PFS

End point description

Clinical PFS (CPFS) was defined as the time from randomization to the first observation of disease progression, either confirmed by CT scans or by clinical evaluation, or death from any cause (as assessed by the independent reviewer with clinical PD considered as an event). Participants without documented progression or death were censored as of the last tumor evaluation determining lack of progression. The analysis population consisted of the FAS.

End point type

Secondary

End point timeframe

End point values	EOX Treatment	EOX+zolbetuximab 800/600 mg/m^2	EOX+zolbetuximab 1000 mg/m^2
Number of subjects analysed	84	77	85
Units: months
median (confidence interval 95%)	4.6 (4.0 to 7.1)	7.5 (5.6 to 11.3)	7.1 (5.6 to 8.0)

CPFS Treatment Comparison (Arm 1 versus Arm 2)

Comparison groups

EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

< 0.0005 ^[9]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.43

Confidence interval

level

95%

sides

2-sided

lower limit

0.29

upper limit

0.65

Notes
[8] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[9] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.

CPFS Treatment Comparison (Arm 1 versus Arm 3)

Comparison groups

EOX Treatment v EOX+zolbetuximab 1000 mg/m^2

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.0085 ^[11]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.38

upper limit

0.83

Notes
[10] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[11] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.

CPFS Treatment Comparison (Arm 3 versus Arm 2)

Comparison groups

EOX+zolbetuximab 800/600 mg/m^2 v EOX+zolbetuximab 1000 mg/m^2

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2904 ^[12]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

1.18

Notes
[12] - The analyses were performed using a 2-sided test at the 5% significance level for the comparison of Arm 3 vs Arm 2.

Secondary: Overall Survival Rate at 12 Months

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End point title

Overall Survival Rate at 12 Months

End point description

Overall survival rate at 12 months after therapy initiation was defined as a proportion of participants alive after 12 months from first dose of any study drug. The analysis population consisted of the FAS.

End point type

Secondary

End point timeframe

Up to 12 months

End point values	EOX Treatment	EOX+zolbetuximab 800/600 mg/m^2	EOX+zolbetuximab 1000 mg/m^2
Number of subjects analysed	84	77	85
Units: percentage of participants
number (confidence interval 95%)	27.4 (18.2 to 37.4)	52.9 (40.8 to 63.6)	37.4 (27.0 to 47.8)

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS was defined as the time from randomization to death from any cause or last contact (if alive). The analysis population consisted of the FAS.

End point type

Secondary

End point timeframe

End point values	EOX Treatment	EOX+zolbetuximab 800/600 mg/m^2	EOX+zolbetuximab 1000 mg/m^2
Number of subjects analysed	84	77	85
Units: months
median (confidence interval 95%)	8.3 (6.9 to 10.2)	13.0 (9.7 to 18.7)	9.6 (8.3 to 11.4)

OS Treatment Comparison (Arm 1 versus Arm 2)

Comparison groups

EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

< 0.0005 ^[14]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.55

Confidence interval

level

95%

sides

2-sided

lower limit

0.39

upper limit

0.77

Notes
[13] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[14] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.

OS Treatment Comparison (Arm 1 versus Arm )

Comparison groups

EOX Treatment v EOX+zolbetuximab 1000 mg/m^2

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.1292 ^[16]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.75

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

1.04

Notes
[15] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[16] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.

OS Treatment Comparison (Arm 3 versus Arm 2)

Comparison groups

EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.128 ^[18]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.73

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

1.02

Notes
[17] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[18] - The analyses were performed using a 2-sided test at the 5% significance level for the comparison of Arm 3 vs Arm 2.

Secondary: Time to Progression (TTP)

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End point title

Time to Progression (TTP)

End point description

TTP was defined as the time from randomization to the first observation of disease progression (based on central reading as assessed by the investigator reviewer). Participants without documented progression were censored as of the last tumor evaluation determining lack of progression. The analysis population consisted of the FAS.

End point type

Secondary

End point timeframe

End point values	EOX Treatment	EOX+zolbetuximab 800/600 mg/m^2	EOX+zolbetuximab 1000 mg/m^2
Number of subjects analysed	84	77	85
Units: months
median (confidence interval 95%)	7.0 (5.7 to 7.7)	9.0 (6.1 to 11.6)	6.9 (5.6 to 8.4)

TTP Treatment Comparison (Arm 1 versus Arm 2)

Comparison groups

EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.0076 ^[20]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.35

upper limit

0.83

Notes
[19] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[20] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.

TTP Treatment Comparison (Arm 3 versus Arm 2)

Comparison groups

EOX+zolbetuximab 800/600 mg/m^2 v EOX+zolbetuximab 1000 mg/m^2

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.0997 ^[22]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

1.06

Notes
[21] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[22] - The analyses were performed using a 2-sided test at the 5% significance level for the comparison of Arm 3 vs Arm 2.

TTP Treatment Comparison (Arm 1 versus Arm 3)

Comparison groups

EOX Treatment v EOX+zolbetuximab 1000 mg/m^2

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.183 ^[24]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.15

Notes
[23] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[24] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.

Secondary: Objective Tumor Response Rate (ORR)

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End point title

Objective Tumor Response Rate (ORR)

End point description

ORR was defined as the fraction of participants with a complete response (CR) or partial response (PR), according to RECIST v1.1 (as assessed by the investigator reviewer). CR according to RECIST v1.1 was defined as the disappearance of all target lesions, any pathological lymph node must have had reduction in short axis to < 10 mm, disappearance of all non-target lesions and normalization of tumor marker level should have occurred as well as no simultaneous appearance of new lesions. PR according to RECIST v1.1 was defined as at least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the screening sum longest diameter and no simultaneous increase in the size of any lesion or the appearance of new lesions should have occurred. The analysis population consisted of the FAS. N is the number of participants with available data.

End point type

Secondary

End point timeframe

Up to week 94

End point values	EOX Treatment	EOX+zolbetuximab 800/600 mg/m^2	EOX+zolbetuximab 1000 mg/m^2
Number of subjects analysed	21 ^[25]	30 ^[26]	26 ^[27]
Units: percentage of participants
number (not applicable)
Based on best response (confirmed)	25.0	39.0	30.6
Based on best response (confirmed and unconfirmed)	33.3	49.4	41.2

Notes
[25] - N=28 for confirmed and unconfirmed
[26] - N=38 for confirmed and unconfirmed
[27] - N=35 for confirmed and unconfirmed

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR)

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End point title

Disease Control Rate (DCR)

End point description

DCR was defined as the fraction of participants with CR or PR or stable disease (SD) according to RECIST v1.1 (as assessed by the investigator reviewer). SD according to RECIST v1.1 was defined as neither sufficient shrinkage to qualify for PR or CR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter recorded since treatment started, measurements must have met the SD criteria at least once after study entry at a minimum interval not less than 6 weeks, no simultaneous increase in the size of any lesion or the appearance of new lesions should have occurred, evaluable lesions must have remained stable or regressed for this category. The analysis population consisted of the FAS. N is the number of participants with available data.

End point type

Secondary

End point timeframe

Up to week 94

End point values	EOX Treatment	EOX+zolbetuximab 800/600 mg/m^2	EOX+zolbetuximab 1000 mg/m^2
Number of subjects analysed	64	64	67 ^[28]
Units: percentage of participants
number (not applicable)
Based on best response (confirmed)	76.2	83.1	78.8
Based on best response (confirmed and unconfirmed)	76.2	83.1	80.0

Notes
[28] - N=68 for confirmed and unconfirmed

No statistical analyses for this end point

Secondary: Duration of Response (DOR)

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End point title

Duration of Response (DOR)

End point description

DOR was determined as the time when criteria for CR or PR were first met until the first date that recurrent or progressive disease or death occurred (as assessed by the independent reviewer). The analysis population consisted of the FAS.

End point type

Secondary

End point timeframe

End point values	EOX Treatment	EOX+zolbetuximab 800/600 mg/m^2	EOX+zolbetuximab 1000 mg/m^2
Number of subjects analysed	84	77	85
Units: months
median (confidence interval 95%)	5.0 (3.2 to 6.7)	7.5 (4.8 to 10.9)	7.6 (4.5 to 11.7)

OS Treatment Comparison (Arm 1 versus Arm 2)

Comparison groups

EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

= 0.0234 ^[30]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.26

upper limit

0.93

Notes
[29] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[30] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.

OS Treatment Comparison (Arm 1 versus Arm 3)

Comparison groups

EOX Treatment v EOX+zolbetuximab 1000 mg/m^2

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

= 0.0854 ^[32]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.29

upper limit

1.09

Notes
[31] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[32] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.

OS Treatment Comparison (Arm 3 versus Arm 2)

Comparison groups

EOX+zolbetuximab 800/600 mg/m^2 v EOX+zolbetuximab 1000 mg/m^2

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.5781 ^[34]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

1.57

Notes
[33] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
[34] - The analyses were performed using a 2-sided test at the 5% significance level for the comparison of Arm 3 vs Arm 2.

Adverse events

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Timeframe for reporting adverse events

From the first dose of study drug administration up to 30 days after the last study medication administration (up to 1791 days).

Adverse event reporting additional description

The total number of deaths (all causes) includes deaths reported after the time frame above.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

EOX Treatment

Reporting group description

Reporting group 1 description

Reporting group title

EOX+zolbetuximab 1000 mg/m^2

Reporting group description

Reporting group 3 description

Reporting group title

EOX+zolbetuximab 800/600 mg/m^2

Reporting group description

Reporting group 2 description

Serious adverse events	EOX Treatment	EOX+zolbetuximab 1000 mg/m^2	EOX+zolbetuximab 800/600 mg/m^2
Total subjects affected by serious adverse events
subjects affected / exposed	27 / 84 (32.14%)	17 / 85 (20.00%)	19 / 77 (24.68%)
number of deaths (all causes)	79	77	63
number of deaths resulting from adverse events	15	9	8
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer recurrent
subjects affected / exposed	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neoplasm malignant
subjects affected / exposed	7 / 84 (8.33%)	4 / 85 (4.71%)	3 / 77 (3.90%)
occurrences causally related to treatment / all	0 / 7	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 7	0 / 4	0 / 3
Neoplasm progression
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Oesophageal adenocarcinoma
subjects affected / exposed	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Injury, poisoning and procedural complications
Remnant gastritis
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Pyloric stenosis
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Arterial thrombosis limb
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vena cava thrombosis
subjects affected / exposed	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Coronary artery insufficiency
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	2 / 84 (2.38%)	0 / 85 (0.00%)	2 / 77 (2.60%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Disease progression
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 84 (1.19%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pyrexia
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Gastrointestinal disorders
Ascites
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	3 / 84 (3.57%)	0 / 85 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 84 (1.19%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 84 (2.38%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary artery thrombosis
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 84 (2.38%)	2 / 85 (2.35%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Respiratory failure
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	2 / 84 (2.38%)	0 / 85 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Infections and infestations
Abscess soft tissue
subjects affected / exposed	1 / 84 (1.19%)	0 / 85 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	0 / 84 (0.00%)	0 / 85 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	2 / 77 (2.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 84 (0.00%)	1 / 85 (1.18%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0

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

Non-serious adverse events	EOX Treatment	EOX+zolbetuximab 1000 mg/m^2	EOX+zolbetuximab 800/600 mg/m^2
Total subjects affected by non serious adverse events
subjects affected / exposed	82 / 84 (97.62%)	83 / 85 (97.65%)	74 / 77 (96.10%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	9 / 84 (10.71%)	1 / 85 (1.18%)	6 / 77 (7.79%)
occurrences all number	11	1	13
Aspartate aminotransferase increased
subjects affected / exposed	11 / 84 (13.10%)	6 / 85 (7.06%)	7 / 77 (9.09%)
occurrences all number	14	6	14
Body temperature increased
subjects affected / exposed	7 / 84 (8.33%)	4 / 85 (4.71%)	3 / 77 (3.90%)
occurrences all number	12	10	14
C-reactive protein increased
subjects affected / exposed	3 / 84 (3.57%)	5 / 85 (5.88%)	3 / 77 (3.90%)
occurrences all number	3	6	3
Gamma-glutamyltransferase increased
subjects affected / exposed	6 / 84 (7.14%)	8 / 85 (9.41%)	9 / 77 (11.69%)
occurrences all number	7	12	11
Lipase increased
subjects affected / exposed	3 / 84 (3.57%)	3 / 85 (3.53%)	4 / 77 (5.19%)
occurrences all number	3	3	4
Weight decreased
subjects affected / exposed	26 / 84 (30.95%)	25 / 85 (29.41%)	25 / 77 (32.47%)
occurrences all number	27	28	25
Vascular disorders
Hypertension
subjects affected / exposed	6 / 84 (7.14%)	5 / 85 (5.88%)	6 / 77 (7.79%)
occurrences all number	7	5	18
Nervous system disorders
Dizziness
subjects affected / exposed	8 / 84 (9.52%)	4 / 85 (4.71%)	4 / 77 (5.19%)
occurrences all number	30	4	15
Headache
subjects affected / exposed	18 / 84 (21.43%)	13 / 85 (15.29%)	12 / 77 (15.58%)
occurrences all number	56	31	68
Neuropathy peripheral
subjects affected / exposed	6 / 84 (7.14%)	0 / 85 (0.00%)	6 / 77 (7.79%)
occurrences all number	8	0	10
Paraesthesia
subjects affected / exposed	9 / 84 (10.71%)	12 / 85 (14.12%)	10 / 77 (12.99%)
occurrences all number	26	15	18
Peripheral sensory neuropathy
subjects affected / exposed	5 / 84 (5.95%)	10 / 85 (11.76%)	5 / 77 (6.49%)
occurrences all number	16	13	10
Polyneuropathy
subjects affected / exposed	4 / 84 (4.76%)	0 / 85 (0.00%)	4 / 77 (5.19%)
occurrences all number	4	0	5
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	30 / 84 (35.71%)	40 / 85 (47.06%)	35 / 77 (45.45%)
occurrences all number	35	59	59
Leukopenia
subjects affected / exposed	14 / 84 (16.67%)	14 / 85 (16.47%)	12 / 77 (15.58%)
occurrences all number	19	28	23
Lymphopenia
subjects affected / exposed	5 / 84 (5.95%)	8 / 85 (9.41%)	3 / 77 (3.90%)
occurrences all number	8	15	6
Neutropenia
subjects affected / exposed	28 / 84 (33.33%)	40 / 85 (47.06%)	33 / 77 (42.86%)
occurrences all number	48	85	70
Thrombocytopenia
subjects affected / exposed	9 / 84 (10.71%)	8 / 85 (9.41%)	11 / 77 (14.29%)
occurrences all number	11	8	14
General disorders and administration site conditions
Asthenia
subjects affected / exposed	19 / 84 (22.62%)	17 / 85 (20.00%)	18 / 77 (23.38%)
occurrences all number	36	37	34
Chills
subjects affected / exposed	2 / 84 (2.38%)	3 / 85 (3.53%)	4 / 77 (5.19%)
occurrences all number	3	3	5
Fatigue
subjects affected / exposed	17 / 84 (20.24%)	21 / 85 (24.71%)	24 / 77 (31.17%)
occurrences all number	31	32	47
Oedema peripheral
subjects affected / exposed	6 / 84 (7.14%)	12 / 85 (14.12%)	10 / 77 (12.99%)
occurrences all number	11	14	14
Pyrexia
subjects affected / exposed	16 / 84 (19.05%)	9 / 85 (10.59%)	9 / 77 (11.69%)
occurrences all number	28	12	12
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	10 / 84 (11.90%)	9 / 85 (10.59%)	14 / 77 (18.18%)
occurrences all number	17	17	24
Abdominal pain upper
subjects affected / exposed	18 / 84 (21.43%)	8 / 85 (9.41%)	7 / 77 (9.09%)
occurrences all number	26	10	9
Ascites
subjects affected / exposed	5 / 84 (5.95%)	4 / 85 (4.71%)	2 / 77 (2.60%)
occurrences all number	14	5	5
Constipation
subjects affected / exposed	6 / 84 (7.14%)	3 / 85 (3.53%)	4 / 77 (5.19%)
occurrences all number	15	7	6
Diarrhoea
subjects affected / exposed	31 / 84 (36.90%)	16 / 85 (18.82%)	13 / 77 (16.88%)
occurrences all number	100	30	32
Dyspepsia
subjects affected / exposed	3 / 84 (3.57%)	4 / 85 (4.71%)	4 / 77 (5.19%)
occurrences all number	9	4	5
Dysphagia
subjects affected / exposed	6 / 84 (7.14%)	2 / 85 (2.35%)	4 / 77 (5.19%)
occurrences all number	7	2	6
Nausea
subjects affected / exposed	64 / 84 (76.19%)	70 / 85 (82.35%)	63 / 77 (81.82%)
occurrences all number	301	389	305
Salivary hypersecretion
subjects affected / exposed	2 / 84 (2.38%)	8 / 85 (9.41%)	5 / 77 (6.49%)
occurrences all number	3	20	8
Stomatitis
subjects affected / exposed	5 / 84 (5.95%)	1 / 85 (1.18%)	3 / 77 (3.90%)
occurrences all number	5	1	3
Vomiting
subjects affected / exposed	46 / 84 (54.76%)	66 / 85 (77.65%)	52 / 77 (67.53%)
occurrences all number	159	348	292
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 84 (2.38%)	4 / 85 (4.71%)	5 / 77 (6.49%)
occurrences all number	4	8	5
Dyspnoea
subjects affected / exposed	4 / 84 (4.76%)	4 / 85 (4.71%)	4 / 77 (5.19%)
occurrences all number	6	7	4
Epistaxis
subjects affected / exposed	5 / 84 (5.95%)	1 / 85 (1.18%)	2 / 77 (2.60%)
occurrences all number	7	1	3
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	17 / 84 (20.24%)	22 / 85 (25.88%)	22 / 77 (28.57%)
occurrences all number	18	22	23
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	6 / 84 (7.14%)	3 / 85 (3.53%)	10 / 77 (12.99%)
occurrences all number	6	3	11
Psychiatric disorders
Insomnia
subjects affected / exposed	3 / 84 (3.57%)	5 / 85 (5.88%)	3 / 77 (3.90%)
occurrences all number	6	7	3
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	6 / 84 (7.14%)	1 / 85 (1.18%)	2 / 77 (2.60%)
occurrences all number	7	1	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	19 / 84 (22.62%)	16 / 85 (18.82%)	15 / 77 (19.48%)
occurrences all number	26	31	19
Hypoalbuminaemia
subjects affected / exposed	5 / 84 (5.95%)	8 / 85 (9.41%)	5 / 77 (6.49%)
occurrences all number	5	9	7

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Were there any global substantial amendments to the protocol? Yes

01 Jun 2012

The changes included: Amendment 1 was issued before the first patient was enrolled into the study. The amendment revised the inclusion criterion related to CLDN18.2 expression in tumor cells.

12 Jun 2013

The changes included: Amendment 2 was issued after approximately 60 patients had been enrolled into each of Arms 1 and 2. This amendment specified the addition of Arm 3

26 May 2014

The changes included: Amendment 3 was issued after 248 patients had been enrolled into the study. The amendment clarified the analysis parameters.

04 Nov 2014

The changes included: Amendment 4 was issued after 252 patients had been enrolled into the study. The amendment specified the addition of the interim analysis.

28 Jul 2015

The changes included: Amendment 5 added a single additional blood draw for patients receiving zolbetuximab for > 12 months to allow for an assessment of adaptive immunity.

26 Jan 2016

The changes included: Amendment 6 condensed the schedule of procedures to facilitate the longer-term follow-up of patients including prolonging the imaging intervals from 6 to 12 weeks and simplifying the follow-up procedures.

11 Sep 2017

The changes included: Amendment 7 changed the study sponsor from Ganymed Pharmaceuticals, Ag to Astellas Pharma Global Development, Inc.

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.

The study was conducted by Ganymed AG, a company that was acquired by Astellas in Dec 2016.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-free Survival (PFS)

Primary: Progression-free Survival (PFS)

Primary: Number of Participants with Adverse Events (AEs)

Primary: Number of Participants with Adverse Events (AEs)

Secondary: Clinical PFS

Secondary: Clinical PFS

Secondary: Overall Survival Rate at 12 Months

Secondary: Overall Survival Rate at 12 Months

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Time to Progression (TTP)

Secondary: Time to Progression (TTP)

Secondary: Objective Tumor Response Rate (ORR)

Secondary: Objective Tumor Response Rate (ORR)

Secondary: Disease Control Rate (DCR)

Secondary: Disease Control Rate (DCR)

Secondary: Duration of Response (DOR)

Secondary: Duration of Response (DOR)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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