FAST: Efficacy and Safety of IMAB362 in Combination With the EOX Regimen for CLDN18.2-positive Gastric Cancer

Sponsor

Astellas Pharma Global Development, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT01630083

Collaborator

(none)

252

Enrollment

Locations

Arms

78.4

Actual Duration (Months)

5.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the trial is to assess the therapeutic effects and the safety profile of IMAB362 combined with EOX (epirubicin, oxaliplatin, capecitabine) as first-line treatment for patients with advanced adenocarcinoma of the stomach, the esophagus or the gastroesophageal junction compared to EOX alone.

Furthermore, sufficient binding of IMAB362 to the target cells is necessary for antitumoral activity. Thus, two dose levels ensuring a serum level above the in vitro predicted clinical efficacy threshold will be investigated.

Condition or Disease	Intervention/Treatment	Phase
CLDN18.2-positive Adenocarcinoma of the Gastroesophageal Junction CLDN18.2-positive Adenocarcinoma of Esophagus CLDN18.2-positive Gastric Adenocarcinoma	Drug: epirubicin Drug: oxaliplatin Drug: capecitabine Drug: zolbetuximab	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

252 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 19, 2012

Actual Primary Completion Date :

Jan 31, 2019

Actual Study Completion Date :

Jan 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: EOX Treatment Participants will receive 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 to be taken in the evening of day 1.	Drug: epirubicin Epirubicin will be administered at a dose of 50 mg/m^2 as a 15-minute intravenous infusion on day 1 of each cycle. Drug: oxaliplatin Oxaliplatin will be administered at a dose of 130 mg/m^2 as a 2-hour intravenous infusion on day 1 of each cycle. Drug: capecitabine The daily dose of capecitabine will be 1250 mg/m^2. Capecitabine tablets to be 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 to be omitted due to administration of zolbetuximab, epirubicin and oxaliplatin.
Experimental: EOX+zolbetuximab 800/600 mg/m^2 Participants will 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 to be administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants will be permitted to continue zolbetuximab monotherapy (600 mg/m^2 every 3 weeks to be 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 is 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 is considered progression.	Drug: epirubicin Epirubicin will be administered at a dose of 50 mg/m^2 as a 15-minute intravenous infusion on day 1 of each cycle. Drug: oxaliplatin Oxaliplatin will be administered at a dose of 130 mg/m^2 as a 2-hour intravenous infusion on day 1 of each cycle. Drug: capecitabine The daily dose of capecitabine will be 1250 mg/m^2. Capecitabine tablets to be 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 to be omitted due to administration of zolbetuximab, epirubicin and oxaliplatin. Drug: zolbetuximab Two different formats of zolbetuximab, comprising different strengths, to be provided. Vials contained 22 mg or 105 mg of zolbetuximab. Prior to administration, zolbetuximab will be reconstituted with 1.1 mL (22 mg zolbetuximab vials) or 5.0 mL (105 mg zolbetuximab vials) water for injection, which will result in a concentration of 20 mg/mL zolbetuximab. The extractable volume per vial will be 1 mL (for 22 mg zolbetuximab vials) or 5 mL (for 105 mg zolbetuximab vials). The reconstituted solution will be further diluted with sodium chloride 0.9% to a final concentration of 2 mg/mL zolbetuximab. Zolbetuximab will be administered as an intravenous infusion over 2 to 3 hours. Other Names: IMAB362
Experimental: EOX+zolbetuximab 1000 mg/m^2 Participants will receive up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab 1000 mg/m^2 intravenously on day 1 of each cycle. Zolbetuximab to be administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants will be 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.	Drug: epirubicin Epirubicin will be administered at a dose of 50 mg/m^2 as a 15-minute intravenous infusion on day 1 of each cycle. Drug: oxaliplatin Oxaliplatin will be administered at a dose of 130 mg/m^2 as a 2-hour intravenous infusion on day 1 of each cycle. Drug: capecitabine The daily dose of capecitabine will be 1250 mg/m^2. Capecitabine tablets to be 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 to be omitted due to administration of zolbetuximab, epirubicin and oxaliplatin. Drug: zolbetuximab Two different formats of zolbetuximab, comprising different strengths, to be provided. Vials contained 22 mg or 105 mg of zolbetuximab. Prior to administration, zolbetuximab will be reconstituted with 1.1 mL (22 mg zolbetuximab vials) or 5.0 mL (105 mg zolbetuximab vials) water for injection, which will result in a concentration of 20 mg/mL zolbetuximab. The extractable volume per vial will be 1 mL (for 22 mg zolbetuximab vials) or 5 mL (for 105 mg zolbetuximab vials). The reconstituted solution will be further diluted with sodium chloride 0.9% to a final concentration of 2 mg/mL zolbetuximab. Zolbetuximab will be administered as an intravenous infusion over 2 to 3 hours. Other Names: IMAB362

Arm

Intervention/Treatment

Active Comparator: EOX Treatment

Participants will receive 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 to be taken in the evening of day 1.

Drug: epirubicin

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

Drug: oxaliplatin

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

Drug: capecitabine

The daily dose of capecitabine will be 1250 mg/m^2. Capecitabine tablets to be 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 to be omitted due to administration of zolbetuximab, epirubicin and oxaliplatin.

Experimental: EOX+zolbetuximab 800/600 mg/m^2

Participants will 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 to be administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants will be permitted to continue zolbetuximab monotherapy (600 mg/m^2 every 3 weeks to be 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 is 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 is considered progression.

Drug: epirubicin

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

Drug: oxaliplatin

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

Drug: capecitabine

Drug: zolbetuximab

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

Other Names:

IMAB362

Experimental: EOX+zolbetuximab 1000 mg/m^2

Participants will receive up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab 1000 mg/m^2 intravenously on day 1 of each cycle. Zolbetuximab to be administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants will be 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.

Drug: epirubicin

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

Drug: oxaliplatin

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

Drug: capecitabine

Drug: zolbetuximab

Other Names:

IMAB362

Outcome Measures

Primary Outcome Measures

Progression-free survival (PFS) [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.]
PFS is 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 will be censored as of the last tumor evaluation determining lack of progression.
Number of Participants with Adverse Events (AEs) [From the first dose of study drug administration up to 30 days after the last study medication administration (up to 1791 days).]
An AE is 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) are those AEs that started or worsened after the first dose of study medication.

Secondary Outcome Measures

Clinical PFS [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.]
Clinical PFS (CPFS) is defined as the time from randomization to the first observation of disease progression, either confirmed by computed tomography (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 will be censored as of the last tumor evaluation determining lack of progression.
Overall Survival Rate at 12 Months [Up to 12 months]
Overall survival rate at 12 months after therapy initiation is defined as a proportion of participants alive after 12 months from first dose of any study drug.
Overall Survival (OS) [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.]
OS is defined as the time from randomization to death from any cause or last contact (if alive).
Time to Progression (TTP) [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.]
TTP is 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 will be censored as of the last tumor evaluation determining lack of progression.
Objective Tumor Response Rate (ORR) [Up to week 94]
ORR is defined as the fraction of participants with a complete response (CR) or partial response (PR), according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (as assessed by the investigator reviewer). CR according to RECIST v1.1 is defined as the disappearance of all target lesions, any pathological lymph node must have reduction in short axis to < 10 mm, disappearance of all non-target lesions and normalization of tumor marker level should occur as well as no simultaneous appearance of new lesions. PR according to RECIST v1.1 is 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.
Disease Control Rate (DCR) [Up to week 94]
DCR is 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 is 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 meet 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 occur, evaluable lesions must remain stable or regress for this category.
Duration of Response (DOR) [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.]
DOR will be determined as the time when criteria for CR or PR are first met until the first date that recurrent or progressive disease or death occurs (as assessed by the independent reviewer).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed adenocarcinoma of the stomach, the esophagus or the gastroesophageal junction
Inoperable locally advanced disease or resections with R2 outcome or recurrent or metastatic disease.
CLDN18.2 expression confirmed by immunohistochemistry in paraffin embedded tumor tissue sample.
Measurable and/or non-measurable disease as defined according to RECISTv1.1
Age ≥ 18 years
Written Informed Consent Form
ECOG performance status (PS) 0-1
Life expectancy > 3 months
HER2/neu negative patients and patients with HER2/neu positive status but not eligible to trastuzumab therapy in discretion of the investigator.
Adequate cardiac, hepatic, renal, hematologic function.

Exclusion Criteria:

Prior severe allergic reaction or intolerance to a monoclonal antibody, to the chemotherapeutics used in this study or any excipient in the respective formulations.
Previous chemotherapy for advanced disease.
Previous perioperative chemotherapy with curative intention within 6 months of start of study treatment. If interval is longer than 6 months (counted from the stop date of the perioperative chemotherapy), patients are allowed.
Known HIV infection or known symptomatic hepatitis (A, B, C).
Symptomatic cerebral metastases.
Pregnancy or breastfeeding.
Previous treatments with maximum cumulative doses of epirubicin > 500 mg/m² and/or other anthracyclines and anthracenediones.
Known dihydropyrimidine dehydrogenase (DPD) deficiency.

Contacts and Locations

Locations

	Site	City	Country
1	Site BUL004	Plovdiv	Bulgaria
2	Site BUL001	Sofia	Bulgaria
3	Site BUL003	Sofia	Bulgaria
4	Site BUL005	Sofia	Bulgaria
5	Site BUL002	Varna	Bulgaria
6	Site CZE002	Olomouc	Czechia
7	Site CZE001	Znojmo	Czechia
8	Site GER012	Bielefeld	Germany
9	Site GER029-01	Bochum	Germany
10	Site GER029	Bochum	Germany
11	Site GER010	Dresden	Germany
12	Site GER001	Essen	Germany
13	Site GER017	Frankfurt	Germany
14	Site GER005	Halle/Saale	Germany
15	Site GER020	Leipzig	Germany
16	Site GER016	Münster	Germany
17	Site GER013	Pinneberg	Germany
18	Site LAT001	Liepaja	Latvia
19	Site LAT002	Riga	Latvia
20	Site RUS011	Arkhangelsk	Russian Federation
21	Site RUS016	Bryansk	Russian Federation
22	Site RUS006	Chelyabinsk	Russian Federation
23	Site RUS007	Ivanovo	Russian Federation
24	Site RUS009	Kursk	Russian Federation
25	Site RUS001	Moscow	Russian Federation
26	Site RUS017	Novgorod	Russian Federation
27	Site RUS002	Obninsk	Russian Federation
28	Site RUS023	Omsk	Russian Federation
29	Site RUS012	Orel	Russian Federation
30	Site RUS014	Orenburg	Russian Federation
31	Site RUS005	Pyatigorsk	Russian Federation
32	Site RUS019	Ryazan	Russian Federation
33	Site RUS003	St.Petersburg	Russian Federation
34	Site RUS010	St.Petersburg	Russian Federation
35	Site RUS015	St.Petersburg	Russian Federation
36	Site RUS013	Yaroslavl	Russian Federation
37	Site UKR003	Dnipropetrovsk	Ukraine
38	Site UKR001	Donetsk	Ukraine
39	Site UKR002	Donetsk	Ukraine
40	Site UKR008	Ivano-Frankivsk	Ukraine
41	Site UKR005	Kharkiv	Ukraine
42	Site UKR007	Kyiv	Ukraine
43	Site UKR006	Lviv	Ukraine
44	Site UKR015	Poltava	Ukraine
45	Site UKR004	Simferopol	Ukraine
46	Site UKR011	Sumy	Ukraine
47	Site UKR010	Uzhhorod	Ukraine
48	Site UKR009	Zaporizhia	Ukraine