Study of AMG 910 in Subjects With CLDN18.2-Positive Gastric and Gastroesophageal Junction Adenocarcinoma

JRCT ID: jRCT2031210242

Registered date:13/08/2021

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Gastric and Gastroesophageal Junction Adenocarcinoma
• Date of first enrollment: 29/06/2020
• Target sample size: 70
• Countries of recruitment: United States,Japan,Austria,Japan,France,Japan,Germany,Japan,Korea, Republic of,Japan,Netherlands,Japan,Spain,Japan,Taiwan,Japan
• Study type: Interventional

Intervention(s)

- Experimental: Cohort 1: AMG 910 6.5 ug
For Cycles 1 and 2, participants received AMG 910 as a short-term intravenous (IV) infusion (approximately 60 minutes) at a dose of 6.5 ug twice a week on Days 1 and 3 of each week in a 28-day cycle. For Cycles 3 to 6, participants received AMG 910 as a short-term IV infusion (approximately 60 minutes) at a dose of 6.5 ug weekly, ie, Days 1, 8, 15 and 22 in a 28-day cycle.
Intervention: Drug: AMG 910

- Experimental: Cohort 1b: AMG 910 6.5 ug
For Cycle 1 Week 1, participants received AMG 910 as an extended IV (eIV) infusion (approximately 96 hours) at a dose of 6.5 ug. For the remainder of Cycles 1 and 2, participants received AMG 910 as a short-term IV infusion (approximately 60 minutes) at a dose of 6.5 ug twice a week on Days 1 and 3 of each week in a 28-day cycle. For Cycles 3 to 6, participants received AMG 910 as a short-term IV infusion (approximately 60 minutes) at a dose of 6.5 ug weekly, ie, Days 1, 8, 15 and 22 in a 28-day cycle.
Intervention: Drug: AMG 910

- Experimental: Cohort 2b: AMG 910 15 ug
For Cycle 1 Week 1, participants received AMG 910 as an eIV infusion (approximately 96 hours) at a dose of 15 ug. For the remainder of Cycles 1 and 2, participants received AMG 910 as a short-term IV infusion (approximately 60 minutes) at a dose of 15 ug twice a week on Days 1 and 3 of each week in a 28-day cycle. For Cycles 3 to 6, participants received AMG 910 as a short-term IV infusion (approximately 60 minutes) at a dose of 15 ug weekly, ie, Days 1, 8, 15 and 22 in a 28-day cycle.
Intervention: Drug: AMG 910

Outcome(s)

Primary Outcome

1. Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT) [ Time Frame: Day 1 to Day 28 ]
All DLTs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. DLTs were defined as any AEs at least possibly related to AMG 910 with an onset within the first 28 days following first dose with any of the following:
- Grade 2 gastric perforation or fistula
- Grade >= 3 non-hematologic AEs including laboratory abnormalities
- Re-challenge with AMG 910 after treatment interruption due to any stomach toxicity results in at least same stomach toxicity and is of CTCAE grade >= 3 or grade 2 and ongoing for more than 3 days despite optimal supportive treatment
- Grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding
- Grade 4 neutropenia lasting > 28 days
- Febrile neutropenia of any grade
- Anemia requiring transfusion per local or international guidelines in the absence of bleeding
- Grade 5 toxicity
- Any other toxicity related to AMG 910 considered significant enough to be qualified as DLT in the opinion of the investigator
2. Number of Participants Who Experienced a Treatment-emergent AE (TEAE) [ Time Frame: Day 1 to 30 days post-last dose; maximum duration was10.97 months ]
A TEAE was defined as any adverse event starting on or after the first administration of investigational product, as determined by the flag indicating if the adverse event started prior to the first dose on the Events case report form, and up to and including 30 days after the last investigational product dose date.
Evaluation of TEAEs included the number of participants with at least 1 TEAE or treatment-related TEAE. Clinically significant changes in vitalsigns, electrocardiogram (ECG) and clinical laboratory tests were recorded as TEAEs.

Secondary Outcome

1. Maximum serum concentration (Cmax) of AMG 910 [ Time Frame: Cycle 1: Days 1-7 at pre-infusion, 1, 2, 4, 24, 48, 72, 96, 120 and 144 hr; Days 8 and 10* at pre-infusion, EOI, 4 and 24 hr post-EOI; Days 15, 17* and 22* at pre-infusion and EOI; Day 24* at pre-infusion, EOI, 2, 4and 24 hr post-EOI (*=Cohort 1 only) ]
Mean Cmax values for the dosing intervals following short-term IV infusion (Cohort 1) and following extended IV infusions (Cohorts 1b and 2b) for Cycle 1 Week 1, and for short-term IV infusions in subsequent dosing intervals in Cycle 1. The timing of the pharmacokinetic (PK) sampling for Week 1 (Days 1 - 7) was based on hours after the start of the infusion and from Day 8 onwards was based on hours after the end of infusion (EOI). Due to the limitednumber of samples obtained and early termination of the study, PK data are summarized for Cycle 1 only.
2. Minimum serum concentration (Cmin) of AMG 910 [ Time Frame: Cycle 1: Days 1-7 at pre-infusion, 1, 2, 4, 24, 48, 72, 96, 120 and 144 hr; Days 8 and 10* at pre-infusion, EOI, 4 and 24 hr post-EOI; Days 15, 17* and 22* at pre-infusion and EOI; Day 24* at pre-infusion, EOI, 2, 4and 24 hr post-EOI (*=Cohort 1 only) ]
Mean Ctrough values for the dosing intervals following short-term IV infusion (Cohort 1) and following extended Iv infusions (Cohorts 1b and 2b) for Cycle 1 Week 1, and for short-term IV infusions in subsequent dosing intervals in Cycle 1 are presented. The timing of the PK sampling for Week 1 (Days 1-7) was based on hours after the start of infusion and from Day 8 onwards was based on hours after EOI. Due to the limited number of samples obtained and early termination of the study, PK data are summarized for Cycle 1 only.
3. Area under the concentration-time curve (AUC) over the dosing interval (AUC0_168hr) [ Time Frame: Cycle 1 Day 1 at pre-infusion, 1, 2, 4, 24, 48, 72, 96, 120 and 144 hr after infusion start and Cycle 1Day 8 pre-infusion through 168 hr post-EOI ]
The timing of the PK sampling for Week 1 (Days 1-7) was based on hours after the start of infusion, and for Day 8 after EOI.
4. Cohort 1 Only: Accumulation Ratio (AR) of AMG 910 [ Time Frame: Cycle 1 Day 8 pre-infusion and Cycle 1 Day 22 pre-infusion ]
5. Half-life (t1/2) of AMG 910 [ Time Frame: Cycle 1: Days 1-7 at pre-infusion, 1, 2, 4, 24, 48, 72, 96, 120 and 144 hr; Days 8 and 10* at pre-infusion, EOI, 4 and 24 hr post-EOI (*=Cohort 1 only) ]
Mean t1/2 values for the dosing intervals following short-term IV infusion (Cohort 1) and following extended IV infusions (Cohorts 1b and 2b) for Cycle 1 Week 1, and for short-term IV infusions in subsequent dosing intervals in Cycle 1 are presented. The timing of the PK sampling for Week 1 (Days 1-7) was based on hours after the start ofinfusion and from Day 8 onwards was based on hours after EOI. Due to the limited number of samples obtained andearly termination of the study, PK data are summarized for Cycle 1 only.
6. Number of Participants With an Objective Response (OR) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [ Time Frame: Day 1 to end of study (EOS); maximum time on study was 18.76 months ]
OR was defined as a best overall response (BOR) of complete response (CR) or partial response (PR) per RECISTv1.1:
- CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm.
- PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sumdiameters. Non target lesions must be non-progressive Disease (non-PD).
7. ORR Per Immune RECIST (iRECIST) [ Time Frame: Day 1 to EOS; maximum time on study was 18.76 months ]
ORR was defined as the incidence of a BOR of immune complete response (iCR) or immune partial response (iPR) per iRECIST:
- iCR: Disappearance of all non-nodal target and non-target lesions and normalization of pathological lymph nodes (whether target or non-target) to <10 mm in short axis.
- iPR: At least a 30% decrease in the sum of measures of target lesions, taking as reference the baseline target lesion sum.
Data was not collected due to early termination of study, therefore data are not available.
8. Duration of Response (DOR) Per RECIST 1.1 [ Time Frame: Day 1 to EOS; maximum time on study was 18.76 months ]
As no participants experienced an objective response, data were not available.
9. DOR Per iRECIST [ Time Frame: Day 1 to EOS; maximum time on study was 18.76 months ]
Data was not collected due to early termination of study, therefore data are not available.
10. Time to progression Per RECIST 1.1 [ Time Frame: Day 1 to EOS; maximum time on study was 18.76 months ]
11. Time to Progression Per iRECIST [ Time Frame: Day 1 to EOS; maximum time on study was 18.76 months]
Data was not collected due to early termination of study, therefore data are not available.
12. Progression-free Survival (PFS) Per RECIST 1.1 [ Time Frame: 6 months and 1 year ]
Data was not collected due to limited follow up time due to study termination, therefore data are not available.
13. PFS Per iRECIST [ Time Frame: 6 months and 1 year ]
Data was not collected due to early termination of study, therefore data are not available.
14. Overall Survival [ Time Frame: 1 year and 2 years ]
Data was not collected due to limited follow up time due to study termination, therefore data are not available.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: <= 99age old
• Gender: Both

Include criteria

1. Subjects with histologically or cytologically confirmed metastatic or locally advanced unresectable gastric or GEJ adenocarcinoma positive for CLDN18.2.
2. Subjects should not be eligible for curative surgery and should have been refractory to or have relapsed after two or more prior lines of standard systemic therapy that included a platinum, a fluoropyrimidine, either a taxane or irinotecan, and an approved vascular endothelial growth factor receptor (VEGFR) antibody/tyrosine kinase inhibitor (TKI) and depending on country-specific standards and approvals.
3. For subjects eligible for human epidermal growth factor receptor 2 (HER2) directed therapy, prior systemic therapy should have included a HER2 targeting antibody approved for treatment of gastric cancer.
4. Subjects may also be included if the aforementioned therapeutic options were medically not appropriate for them. In these cases, the reason(s) why required prior therapies for gastric cancer were medically not appropriate should be documented in the subject's electronic case report form (eCRF).
5. For dose-expansion only: Subjects with at least 1 measurable lesion greater than or equal to 10mm which has not undergone biopsy within 3 months of screening scan. This lesion cannot be biopsied at any time during the study.
6. Subjects with stable condition and anti-coagulative therapy ongoing for at least 1 month, no obvious signs and symptoms of bleeding, and coagulation parameters are fulfilled.
7. Subjects should be able to use proton pump inhibitors.

Exclude criteria

1. Any anticancer therapy or immunotherapy within 4 weeks of start of first dose (14 days for palliative radiation).
2. Untreated or symptomatic central nervous system (CNS) metastases, leptomeningeal disease, or spinal cord compression
3. Autoimmune disorders requiring chronic systemic steroid therapy or any other form of immunosuppressive therapy while on study, eg, ulcerative colitis, Crohn's disease, or any other gastrointestinal autoimmune disorder causing chronic nausea, vomiting, or diarrhea. Recent or current use of inhaled steroids or physiological substitution in case of adrenal insufficiency is not exclusionary.
4. Evidence or history within last 3 months of gastrointestinal inflammatory conditions not associated with the underlying cancer disease including gastrinomas, duodenitis, proven gastric ulcer, duodenal ulcer, pancreatitis, or subjects with recent gastric bleeding. Subjects may be included if the symptomatic/immunosuppressive treatment is discontinued more than 4 weeks prior to the first dose of AMG 910, symptoms have resolved, and gastroscopy does not indicate signs of active disease.
5. Subjects with inherited bleeding disorders (eg, Willebrand's disease, hemophilia A and other clotting factor deficiency) and subjects with known heparin-induced thrombocytopenia.
6. Subjects requiring non-steroidal anti-inflammatory drugs (NSAIDs) during study treatment. The NSAID(s) should be stopped within 7 days prior to start of treatment.

Related Information

• Primary Sponsor: Shimonaga Masahiro
• Secondary ID(s): NCT04260191